Page 66 – Practical Gastro

A Case Report

Pre-Emptive Embolization For Post Liver Biopsy Asymptomatic Type 2 Hepatoportal Fistula

March 2016 • Volume XL, Issue 3

A hepatoportal fistula is an abnormal communication between the hepatic artery and the portal vein that may be congenital or acquired. Often the fistula is small and asymptomatic, however, in rare instances the fistula may grow in size and become clinically significant. We present a case of a moderate to large, asymptomatic type 2 hepatoportal fistula developing after liver biopsy and its management.

Youran Gao, MD¹ Craig Greben, MD² Tai-Ping Lee, MD³ ¹Department of Internal Medicine ²Department of Interventional Radiology ³Department of Gastroenterology and Hepatology North Shore – LIJ, Manhasset, NY

INTRODUCTION

Hepatoportal fistulas are arteriovenous communications between the splanchnic artery and the portal vein that can be either congenital (type 3) or acquired (type 1 small peripheral, type 2 large central).¹ Type 1 fistulas are usually transient and asymptomatic, whereas type 2 fistulas can cause portal hypertension complicated by variceal bleed or ascites. Herein, we describe a case of a patient who developed a moderate to large fistula after liver biopsy which was embolized with n-butyl-2-cyanoacrylate (NBCA) prior to developing symptoms.^2,3

CASE

A 75 year-old woman with autoimmune hepatitis with overlap syndrome was seen at a follow up clinic visit. She underwent an ultrasound guided left lobe liver biopsy one year prior for worsening liver enzymes. The biopsy, which was without complication, confirmed chronic hepatitis with prominent mononuclear portal inflammation. Her liver enzymes returned to baseline within three months without specific intervention. Upon her return to the hepatology clinic one year after liver biopsy, a routine ultrasound of the abdomen was performed. The ultrasound showed a moderate to large communication of the left hepatic artery with the left portal vein with reverse flow on color Doppler ultrasonography. Magnetic resonance imaging (MRI) with contrast confirmed the presence of a moderate sized communication between the left hepatic artery and the left portal vein. Injection of contrast showed retrograde flow into a branch of the portal vein. Although the patient was asymptomatic, she was referred to interventional radiology for embolization due to the size of the fistula. Segment 2 of the left hepatic artery was successfully embolized using 0.3 cc 40% n-butyl- 2-cyanoacrylate (NBCA). A post embolization contrast study demonstrates elimination of fistula. The procedure was without complications and well tolerated.

DISCUSSION

The first instance of hepatoportal fistula was described by Goodhard in 1889.⁴ It is an aberrant communication between the hepatic artery and the portal vein. Etiologies include congenital, blunt or penetrating trauma, rupture of the hepatic artery, iatrogenic causes (liver biopsy, percutaneous biliary drainage, surgery, etc), hepatitis, neoplasm and infections.⁵ If the fistula becomes large enough it may lead to reverse flow from the hepatic artery to the portal vein bypassing the sinusoids. This leads to portal hypertension and its sequelae including ascites and variceal bleeding.

Liver biopsy plays an important role in managing patients with chronic liver diseases. Type 2 hepatoportal fistula is a rare but serious complication from liver biopsy. The first case was reported by Preger in 1967 and since then the occurrence rate after liver biopsy is around 5-10% with majority of them small and located peripherally.⁶ Doppler ultrasound showing communication with arterial and portal vein and possible reversal of flow is usually the initial screening modality. Computed tomography (CT) or MRI.

Moderate to large Type 2 hepatoportal fistulas have a higher chance of progressing. Early detection and treatment should be taken before liver damage and portal hypertension takes place. Surgical ligation of the communication has been replaced by endovascular transcatheter arterial embolization.⁷ Agents such as stainless steel microcoils and NBCA all have yielded good results with low complication rates.⁸

In our case, we demonstrate the importance of color Doppler ultrasonography in detection of hepatoportal fistulas. It highlights the need to do serial ultrasounds with Doppler after liver biopsies. A hepatoportal fistula that is changing in size, moderate or large should be considered for radiological guided embolization. Pre-emptive treatment using NBCA for embolization can prevent development of portal hypertension and its complications.

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Liver Disorders, Series #5

Extra Hepatic Manifestations of Liver Diseases

March 2016 • Volume XL, Issue 3

Pavithra Indramohan,

Elie Aoun

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Patients with liver disease present with varying severity ranging from being asymptomatic with abnormal liver function tests to those patients with overt florid liver failure. This paper will review extrahepatic features of liver diseases.

Pavithra Indramohan, MD, Elie Aoun, MD Allegheny Health Network, Division of Gastroenterology, Pittsburgh, PA

INTRODUCTION

The liver is the largest organ in the body and conducts a myriad of vital metabolic and excretory functions. In addition, by virtue of its circulatory relationship to the absorptive surface of the gastrointestinal tract, the liver is the initial site where ingested materials entering via the gastrointestinal tract, such as drugs and bacterial metabolites are processed. Hepatocytes perform the function of homeostasis.¹ Dysregulation of the liver or hepatocytes thus produces clinical effects that are limited not only to the liver, but can also cause derangement in the internal mileu, thereby contributing significantly to mortality and morbidity in liver disease patients. The clinical syndrome produced by hepatic injury may include systemic manifestations and evidence of injury not limited only to the liver. It is therefore essential to recognize the various extra- hepatic features of liver diseases for timely management of these disorders. Patients with liver disease present with varying severity ranging from being asymptomatic with abnormal liver function tests to those patients with overt florid liver failure. This paper will review extrahepatic features of liver diseases.

Effects of Liver Diseases on the Heart

In patients with cirrhosis, there is increased arteriovenous (AV) shunting thereby increasing the resting cardiac output, left ventricular diastolic diameter, and mean velocity of the left ventricular wall. There is also decreased peripheral resistance and oxygen consumption related to AV shunting.² However, these effects are reversible after transplantation. Long- term estrogen and anabolic steroids use may aggravate preexisting vasculopathy, inducing sinusoidal dilation and subsequent peliosis hepatis and should be considered in the differential of high output failure in liver disease.³

The prevalence of myocardial infarctions is found to be lower in cirrhotic patients than in the general population. For mechanisms that remain unclear but are probably related to cholesterol metabolism, there is a protective effect on atherosclerosis in patients with cirrhosis, with exceptions being in patients with nonalcoholic steatohepatitis (NASH) and hepatitis C virus (HCV)-related cirrhosis.^4,5 It has been found that HCV is an independent risk factor for accelerated atherosclerosis in cirrhotic patients. Similarly, it is reported that the prevalence of all coronary artery disease risk factors are significantly higher in NASH- related cirrhotic patients.⁶

There is paucity of data regarding the incidence of HCV infection in non-ischemic cardiomyopathy, although the association of dilated and hypertrophic cardiomyopathies with HCV have been reported widely. In some genetically predisposed individuals, HCV core protein may damage the myocardium through either direct or indirect immunological mechanisms.^7,8 Fibrinous pericarditis, characterized by the presence of fibrinous exudates in the pericardial sac that are sometimes accompanied by a small amount of serous effusion, has also been described in patients with cirrhosis, although the underlying pathophysiology is poorly understood. It has been found that pericarditis can occur even in the absence of uremia as a result of decompensated liver disease.⁹

Effects of Liver Diseases on the Respiratory System

Patients with liver diseases may exhibit dyspnea due to a variety of cardiopulmonary alterations. Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPHTN) are two pulmonary vascular complications of liver disease manifesting as dyspnea. A careful evaluation of concomitant symptoms, physical examination, pulmonary function testing including an arterial blood gas analysis, echocardiographic imaging, and hemodynamic studies are useful for differentiating between these conditions and is crucial for selecting transplant candidates.¹⁰ HPS, occurring in 5%-32% of cirrhotic patients, is a triad of decompensated liver disease, arterial deoxygenation due to pulmonary gas exchange abnormalties, and evidence of intrapulmonary vascular dilatation (IPVD).¹¹ Arterial desaturation (a resting PA-a,O2 ≥15mmHg and ≥ 20 mmHg in patients 64 yrs) is due to increased intrapulmonary shunting (99Tc MAA shunting index > 6%) without evidence of pulmonary arterial hypertension. Intrapulmonary vascular dilatation can be diagnosed by transthoracic contrast enhanced echocardiography (CE TTE), technetium 99m labeled macroaggregated albumin (99Tc MAA) scan and pulmonary arteriography. Contrast enhanced transthoracic echocardiography is considered the gold standard for the diagnosis of HPS with detection of microbubbles within the left atrium considered to be a positive CEE.^11,12 Orthotopic liver transplant can be considered in severe cases and is the most effective treatment.¹³

PPHTN is associated with portal hypertension without evidence of intrapulmonary shunting (99Tc MAA < 6%) and intravascular pulmonary vascular dilation differentiating it from HPS. Although the mechanism of PPHTN remains unclear, it is thought to be due to accumulation of under-metabolized vasoactive substances in the pulmonary circulation. Orthotopic liver transplantation can worsen PPHTN and can lead to acute right ventricular failure. It is therefore contraindicated in patients with PPHTN, which makes distinguishing HPS from PPHTN critical prior to liver transplant.^14,15

Chronic HCV is associated with idiopathic pulmonary fibrosis and the cumulative rate of development is 0.9% at 20 years after HCV infection.¹⁶ This is evidenced by the higher frequency of HCV markers in IPF patients, an increase in lymphocyte and neutrophil numbers in bronchoalveolar lavage of HCV chronic infection patients.¹⁷

Effects of Liver Diseases on the Nervous System

The relationship between the functional status of the liver and that of the brain has been known for centuries.¹⁸ There are both central and peripheral neurological manifestations of liver diseases. For the purpose of understanding the central nervous system presentations, hepatic encephalopathy related and non hepatic encephalopathy-related changes will be reviewed.

Hepatic Encephalopathy Associated Central Nervous System Damage

Hepatic encephalopathy is a spectrum of neuropsychiatric damage ranging from inversion of sleep rhythm to deep coma. It can occur both in acute or chronic liver diseases. It is widely thought that the pathogenesis of hepatic encephalopathy is multifactorial. Currently, the two factors considered to be most important in pathogenesis are raised brain concentration of ammonia and increased GABA mediated neurotransmission. Ammonia is normally metabolized by cerebral astrocytes by converting glutamate to glutamine. However in hepatic encephalopathy, due to excess ammonia, there is an excess production of glutamine that causes the astrocytes to swell resulting in the neuropsychiatric manifestations of hepatic encephalopathy.¹⁹ Potential mechanisms for increased inhibitory neurotransmitter GABA in hepatic encephalopathy include increased availability of GABA in synaptic clefts or increased blood to brain transfer of GABA and increased brain concentrations of natural benzodiazepine receptor agonist ligands.^20,21 Hepatic encephalopathy has been classified into 4 stages based on the severity of the symptoms (Table 1). Stage I is the mildest form and includes symptoms such as mild confusion, and Stage IV is the most advanced and severe form, which includes coma.^22,23

Precipitating factors for hepatic encephalopathy include hypokalemia, hyponatremia, metabolic alkalosis, hypoglycemia, gastrointestinal bleeding, constipation, sedatives, tranquilizers, infection and portosystemic shunts (spontaneous, surgical, TIPS).²⁴

Asterixis or “liver flap” is often present in the early stages of hepatic encephalopathy. Asterixis consists of infrequent involuntary flexion-extension movements of the hand (one flap every one to two seconds), which may result in part from an impairment of the normal inflow of joint position sense to the brain stem reticular formation. Asterixis should be classified as a negative myoclonus rather than a tremor.²⁰

Recognizing and treating hepatic encephalopathy is important, because data from the Healthcare Cost and Utilization Project (HCUP) show that hepatic encephalopathy is associated with substantial healthcare utilization and costs.²⁵ Some management strategies include: 1) dietary protein restriction to reduce the ammonia load, 2) non absorbable disaccharides, 3) gut antibiotics like rifaximin, 4) branched chain AA, and 5) use of the GABA inhinitor, flumenazil. Non- absorbable disaccharides were shown to be inferior to antibiotics in reducing ammonia levels, but there was no significance in mortality between the two treatment groups.²⁶ Data suggest a significant improvement in cognitive function following liver transplantation, but patients do not return to normal.

Acquired (non-Wilsonian) hepatocerebral degeneration (AHCD) is a clinico-pathological syndrome of brain dysfunction resulting from repeated attacks of hepatic encephalopathy.²⁷

Non-Hepatic Encepahalopathy Related Central Nervous System Damage

Under this entity, Wilson’s disease is the best known. Others include congenital diseases like Reye’s syndrome, congenital hyperammoniemia, kernicterus, galactosemia, porphyrias, Zellweger syndrome.²⁰

Wilson’s disease is an autosomal recessive neuropsychiatric disorder that occurs due to excessive accumulation of copper in various organs, particularly the liver and brain. Psychiatric manifestations of Wilson’s disease are protean, but are predominantly personality changes. Four basic categories of disturbance have been described: behavioral/personality, affective, schizophrenia-like, and cognitive dysfunction. The neuropsychiatric manifestations such as dysarthria, dyspraxia, ataxia, a tremor-rigidity syndrome and psychoses, and progressive extrapyramidal neurological disorder are characteristic of Wilson’s disease.^28,29 Hepatitis A infection can also result in encephalomyelitis.³⁰ It is also reported that chronic HCV infection results in neurocognitive damage secondary to the neuroinvasion of microglia by HCV.³¹ Hepatic myelopathy is characterized by spastic paraparesis with minimal sensory involvement. It is mainly due to symmetrical demyelination, predominantly of the lateral pyramidal tracts, sometimes associated with axonal loss from the cervical cord level. It is thought to be secondary to nitrogenous products bypassing the liver through the porto-caval shunt in advanced hepatic encephalopathy.³²

Gullian Barre syndrome is associated with HBV and rarely in HCV infection due to immune complex deposition in these infections.³³ The precise incidence, severity and characteristics of neuropathy, and the relationship of neuropathy to different etiologies of liver disease have not been defined. Peripheral neuropathy may be observed in patients with cryogloblunemia in HCV infection, and usually is a moderate axonal sensory polyneuropathy. It is also seen in other conditions like porphyrias and alcoholic liver diseases. Sensory neuropathy is also a common manifestation of primary biliary cirrhosis. This contributes to hyperesthesia leading to itching seen in primary biliary cirrhosis. In addition, autonomic dysfunction presenting as reduced 24-hour heart rate variability is also seen in primary biliary cirrhosis.^{13, 34}

Effects of Liver Diseases on the Skin

Understanding and recognizing skin changes that can occur in patients with liver failure is essential, as it often leads to prompt diagnosis and treatment of the underlying liver disease. For instance, jaundice, the cardinal sign of hyperbilirubinemia, is usually seen when serum bilirubin levels exceed 2.5 or 3.0 mg/dL.³⁵ The color of the skin typically reflects the severity of the bilirubin elevation. Another sign of an underlying liver disorder is evidence of xanthelasma, which is a painless yellow soft plaque that occurs due to localized deposition of cholesterol underneath the skin usually beneath the eyelids. another skin-related disorder occurring in patients with an underlying liver condition include hyper-pigmentation or a slate-gray discoloration of the skin, which occurs in cirrhosis, but more specifically in hemochromatosis. This is due to iron deposition in the skin and hence called as Bronze diabetes. Hyper-pigmentation should be contrasted with hypo-pigmented macules called Bier’s spots, which can also occur in liver diseases, secondary to venous stasis from damage to the small vessels. These however disappear on pressure and limb elevation.^35,36

Pruritus

Until recently, it was thought that pruritus caused during liver disease was related to toxins deposited in the skin. However, studies now suggest that neural events originating from the CNS may cause pruritus. It has been observed that the central opioidergic tone is increased in cholestasis causing pruritus, and hence opiate antagonists ameliorate the pruritus of cholestasis.³⁷ In fact, studies have demonstrated a striking opioid withdrawal- like syndrome induced by the oral administration of a potent opiate antagonist, which further illustrates that increased central opioidergic tone is the cause of pruritis in patients with chronic cholestatic liver disease. Although pruritus is generally resistant to therapy, anion exchange resin cholestyramine, rifampicin, and opioid antagonist naltrexone have been used with varying success. Plasmapharesis has been used successfully in resistant cases, and liver transplantation has been shown to ameliorate pruritus completely.³⁸

Prurigo Nodularis

Another skin condition, prurigo nodularis, which are intensly pruritic, firm, crusty nodules, have been observed in patients with hepatitis C infection. These nodules lead to itching, excoriation and diffuse scarring. Corticosteroid cream, antihistamine, and low-dose thalidomide, and tumor necrosis factor (TNF) antagonist have been used to control symptoms.³⁵

Lichen Planus

Also seen in patients with hepatitis C infection are lichen planus, which are planar, polygonal, purplish pruritic papules occurring anywhere on the body, but are most prominent on the wrists and ankles. In approximately 85% of affected individuals, the papules usually resolve by 18 months. A subtype of this skin disorder, called lichen planopilaris, occurs on the scalp and results in permanent hair loss.³⁹

Vitiligo

Vitiligo is an autoimmune destruction of the melanocytes, and it manifests as depigmented, irregular, white patches. It occurs in primary biliary cirrhosis and also in patients with hepatitis C infection who are being treated with interferon. Interferon-induced vitiligo resolves after treatment cessation.³⁵ Porphria Cutanea Tarda results from a deficiency of the hepatic enzyme uroporphyrin decarboxylase. This causes a photochemical reaction that generates reactive oxygen species that activate uroporphyinogen deposited in the skin, thus leading to the characteristic skin blistering. In 50% patients with hepatitis C in sun-exposed areas, as the blisters heal, keratin filled milial cysts develop in these areas of ulceration.^13,40

Dupuyntren’s Contracture

Dupuyntren’s contracture is the fibrotic thickening of the palmar fascia, resulting in painless stiffness, curling and loss of function of the involved fingers. Although the pathogenesis is unknown, it is usually observed in patients with alcoholic liver diseases. It is amenable to correction by surgery, radiation, simvastatin, or N acetyl cysteine. Facial lipodystrophy is also seen in alcoholic liver disease due to malnutrition.^17,41

Cutaneous Vascular Signs

The most common cutaneous vascular sign are echymoses, which occur due to easy bruising secondary to platelet function abnormalities in cirrhosis. Spider vessel, usually in the area drained by the superior vena cava. It is due to an accumulation of free estradiol in patients with liver diseases causing these vessels to dilate and is associated with coexisting gastric and esophageal varices. Therefore, the presence of echymoses should prompt the clinician for endoscopic work up in liver disease.⁴² Papermoney skin, a random scattering of needle-thin thread-like capillaries in the upper trunk resembling American dollar bills, occurs in association with spider angiomas. Palmar erythema is a crimson discoloration of the palms and fingertips, more in the hypothenar eminence occurring in liver disease. It is thought to be secondary to localized increase in nitric oxide and prostacyclins resulting in vasodilation and erythema.³⁶ Advanced liver disease can cause thinning and loss of hair. Similarly, it can also cause thinning and damage of the nails. It can lead to clubbing, onycholysis and leuconychia. Terry’s nails, which is a ground glass opacity of the proximal 2/3 of the nails can also occur in patients with cirrhosis.^35,43

Effects of Liver Diseases on the Renal System

Renal manifestations in liver diseases could be hepatitis- associated nephropathy or hepatorenal syndrome from cirrhosis, and it is essential to differentiate both.

Hepatorenal Syndrome(HRS)

The incidence of HRS is close to 40 % after 5 years of cirrhosis. Patients with ascites having dilutional hyponatremia secondary to renal retention of sodium are at an increased risk for HRS.^44,45 Based on the rapidity of progression of renal failure, they are classified as having Type1 or type 2 failure. The predominant clinical feature of patients with type 1 HRS is severe renal failure, and that of patients with type 2 HRS is recurrent ascites. The mechanism is due to increased splancic vasodilation in portal hypertension. This leads to arterial underfilling, triggering the vasoconstrictive compensatory mechanisms including the renal vasculature, thereby decreasing renal perfusion contributing to HRS.⁴⁶ The initial approach to these patients with renal failure, begins with urinalysis. The diagnosis of HRS is being made in the absence of parenchymal kidney disease, proteinuria <500 mg/d with elevated creatinine in a patient with cirrhosis with ascites in the absence of shock. Treatment includes volume expansion and vasoconstricting agents to improve the extremely dilated splancic bed and to suppress the endogenous renal vasoconstriction for improved renal circulation. The survival expectancy is dependent on the type of HRS and the severity of liver disease. Even with liver transplant, the 3-year survival is lower in comparison with those patients with no HRS. In type 1, hospital survival is less than 10% and the expected median survival time only 2 weeks. By contrast, patients with type 2 have a much longer median survival time.^44,45

Hepatitis Associated Renal Disease

Hepatitis B is directly associated with membranous nephropathy and membranoproliferative glomerulonephritis (MPGN). HBV-related MPGN is due to immune complex deposition in the mesangium and subendothelial space. Antiviral treatment with lamivudine or interferon induces complete remission.^47,48 Nephrotic syndrome secondary to HBV-related membranous nephropathy resolves spontaneously in children unlike in adults, which does not respond to antiviral treatment either.¹³

The incidence of mixed cryoglobulinemia, MPGN and membranous nephropathy is more common with HCV than HBV. The pathogenesis of HCV related cyroglobulinemic MPGN is due to glomerular damage caused by immune complex deposition of HCV, IgG and IgM rheumatoid factors.⁴⁹ The combination treatment of peginterferon and ribavarin has been shown to effectively cause sustained virologic response, resolution of proteinuria along with improvement in creatinine levels. Rituximab has also been shown to be successful in improving glomerular nephritis.⁵⁰

Effects of Liver Diseases on the Blood
Platelet Abnormalities

Thrombocytopenia alone or in combination with other cytopenias is the most common cytopenia associated with liver disease and occurs in up to 77% of patients with cirrhosis.⁵¹

Multiple mechanisms involving decreased production and increased peripheral destruction contribute to this abnormality. Thrombopoietin is produced in the liver and it can be decreased in liver failure along with a decreased function of the synthesized platelets. Increased peripheral destruction could be related to splenic sequestration or antibody mediated as in HCV. High affinity binding of HCV to platelet membrane with subsequent binding of anti- HCV antibody with subsequent phagocytosis causes thrombocytopenia. They usually present as chronic ITP with anti-HCV antibodies positive in 10-30% of these patients.⁵² Moderate thrombocytopenia also develops following orthotopic liver transplantation in the first week with gradual resolution in the second week and requires only supportive care. However persisting or worsening thrombocytopenia may be due to sepsis, graft dysfunction, persistent portal hypertension or hypersplenism.^53,54

AST/ platelet ratio (APRI) is a predictor of liver failure in HBV infection and recurrent HCV after transplantation. APRI values of ≤0.3 and ≤0.5 rule out significant fibrosis and cirrhosis, and a value of ≥1.5 is indicative of significant fibrosis. In patients with NAFLD, APRI values tend to increase with the degree of fibrosis, suggesting that it could be useful in this disease. APRI appears to be of no value in patients with autoimmune hepatitis.⁵⁵

Platelet count to spleen diameter (PC/SD) ratio less than 909 is one of several parameters proposed for the noninvasive prediction of esophageal varices.⁵⁶

Coagulopathy

Coagulation factors are synthesized in the liver and can cause abnormal coagulation in liver disease similar to DIC. A decreasing trend in factor VIII, fibrinogen and platelets is however more consistent with DIC as factor VIII is not produced in the liver. It also causes prolongation of PT, hyperfibrinolysis, dysfibrinogenemia all increasing the incidence of bleeding in liver diseases.⁵⁷ Budd Chiari syndrome is hepatic vein obstruction at various levels from either thrombosis or fibrosis. Patients should undergo a hypercoagulable workup for protein C, protein S deficiencies, factor V Leiden mutations, lupus anticoagulant, prothombin gene mutataion and antiphospholipid antibody syndrome.^58,59 Paroxysmal nocturnal hemoglobinuria should be considered as a possibility when a patient presents with Budd Chiari syndrome -associated with pancytopenia.⁵³ Hepatocellular carcinoma is the most common cause of portal vein thrombosis but non- malignant PVT incidence is reported in 0.6 to 12% of patients with cirrhosis.⁵⁹ It can be asymptomatic or it may present with worsening of liver disease and complicates the procedure of liver transplantation. Decreased portal flow, previous abdominal surgery and sclerotherapy are identified as causes of portal vein thrombosis. If underlying inherited disorders are suspected, a thorough evaluation should be done prior to liver transplant, as it can increase the risk of post- operative venous thrombosis.⁵⁴

Erythrocyte Abnormalities

Anemia in liver diseases is multifactorial. Defective production of red blood cells could be due to nutritional deficiencies along with myelosuppression. It could also be due to acute blood loss in variceal hemorrhage. Hemolytic anemia occurs as spur cell anemia in NASH and alcohol liver disease, ribavarin induced hemolysis, autoimmune hemolytic anemia in autoimmune hepatitis. Sideroblastic anemia is seen in Wilson’s disease secondary to treatment with trientene.^13,60

Leuckocyte Abnormalities

Leucopenia occurs in cirrhosis secondary to splenic sequestration, due to circulating hematopoietic progenitor inhibitory factors, increased apoptosis or interferon related mechanisms. Decrease in lymphocytes is probably related to chronic malnutrition.^13,60

There is an increased risk of non Hodgkin’s lymphoma in HCV due to increase monoclonal proliferation of B cells in HCV.⁶¹

Endocrine and the Liver

Endocrine disorders maybe coexistent with underlying liver diseases. We will highlight only the endocrine manifestations of liver diseases.

Thyroid Dysfunction in Liver Disease

Various liver diseases can have differing effect on thyroid hormone metabolism.

Cirrhosis usually produces sick euthyroid syndrome. As thyroxine- binding globulin is a positive acute phase reactant, total T4 levels are elevated with normal freeT4 levels in acute hepatitis. Primary biliary cirrhosis and autoimmune hepatitis also have associated autoimmune thyroid diseases. Primary sclerosing cholangitis is associated with Hashimoto’s thyroiditis, Grave’s disease and Reidel’s thyroiditis. HCV can cause thyroid disorders including cancer, independent of interferon treatment.⁶²

Anti-thyroid antibodies are also seen in 14.7% of women with chronic HCV infection. Hence it is essential to screen these patients for thyroid diseases before treatment.⁶³

Hypothyroidism is also seen with transcatheter arterial chemoembolization and sorafenib used for hepatocellular carcinoma treatment. Severe diuretic resistant ascites can sometimes occur in uncontrolled hypothyroid cirrhosis. Thyroid hormone replacement therapy results in regression of the ascites over a few months. Hypothyroidism should be considered in patients with portal hypertension when they present with diuretic resistant ascites, and hormone replacement therapy often makes them diuretic sensitive.⁶²

Diabetes Mellitus, Lipids and the Liver

The development of diabetes mellitus, metabolic syndrome and NAFLD is interlinked. HCV infection is thought to produce diabetes by increasing the insulin resistance. This defective insulin signaling causes increased free fatty acid oxidation and triglyceride accumulation within the liver causing steatosis. This triggers the inflammatory cascade causing stellate cell activation and the resultant hepatic fibrosis. This makes diabetes mellitus and concominant HCV infection increase the development of hepatocellular carcinoma.62,64

Screening for diabetes mellitus should be performed on all HCV patients and the use of hepatotoxic oral hypoglycemic agents should be used with caution in these patients. Biguanides, which improve insulin resistance, and alpha glucosidase inhibitors, which improve post prandial hypoglycemia, can be used in this population. that makes them susceptible for central obesity further aggravating the insulin resistance.⁶⁵ There is also a 2.3% risk associated hypopituirasim in patients with NAFLD.¹³

Adrenal Diseases and the Liver

There is 33 – 66% relative adrenal insufficiency (RAI) in liver failure and the degree of adrenal dysfunction correlates with the severity of liver diseases. It is seen even after orthotopic liver transplantation in the absence of sepsis. There are improved outcomes with corticosteroid supplementation.⁶² However they should be reserved only for patients with sepsis requiring vasopressors and at this point recommendations await further research.

Liver Diseases and Nutrition

The incidence of protein-energy malnutrition in liver disease is between 30 – 90% and is associated with adverse survival outcomes. Several studies have shown that the severe degree of malnutrition was associated with adverse outcomes even after transplantation.⁶⁶

Polyunsaturated fatty acid synthesis (PUFA) from essential fatty acid precursors occur in the liver. PUFA contributes to the fluidity of the cell membranes. PUFA deficiency occurs in cirrhosis and is an independent predicator of mortality of alcoholic cirrhosis. Hepatic glycogen stores are depleted in chronic liver diseases and produces severe catabolic state. Branched chain amino acids (BCAA) has shown to improve energy metabolism, reduce malnutrition, improve liver function tests and quality of life in cirrhosis.⁶⁷ However, as it may exacerbate glucose intolerance, the use of alpha glucosidase inhibitors with it is encouraged.

Hence it is important to diagnose these nutritional deficiencies early to improve mortality. The European Society for Nutrition and metabolism guidelines state that subjective global assessment, anthropometry or hand grip strength are sufficient to identify undernutrition in this population.⁶⁸ An intake of 35- 40 kcal/Kg/day (dry body weight) and 1.2-1.5 g/ kg/ day of protein, with low sodium content(<2g/day) combined with supplementation in small frequent meals is generally recommended in these patients.⁶⁹

Effects of Liver Diseases on Other Organ Systems

Advancing liver disease is associated with bone loss so improved disease progression may improve bone loss. The pathogenesis is similar to post menopausal and age related bone loss with estrogen deficiency. The other factors that either directly or indirectly alter bone mass such as insulin growth factor-1 (IGF-1) deficiency, hyperbilirubinemia, alcoholism, excess tissue iron deposition, subnormal vitamin D levels, vitamin D receptor genotype, osteprotegerin deficiency, and immunosuppressive therapy preceding and following liver transplantation. High turnover osteoporosis has been described among 20% to 30% of patients with chronic cholestatic liver disease, primary biliary cholangitis, and primary sclerosing cholangitis.⁷⁰ Acclerated osteoporosis has also known to occur in chronic prednisone use in the setting of autoimmune hepatitis and post orthotopic liver transplantation for immunosuppression. Arthritis maybe the first manifestation of liver disease and it is also the most common extrahepatic manifestation in primary biliary cirrhosis, autoimmune hepatitis and hemochromatosis.⁷⁰

Ophthalmic System

The early recognition of the eye signs can help in prompt diagnosis of the underlying liver diseases. Keratoconjunctivitis sicca is particularly common in 50% of patients with primary biliary cirrhosis and 35% of patients with active hepatitis.

Corneal clouding combined with hepatomegaly is a feature of several types of storage disorders. The Kayser Fleischer ring, which is a yellow, red, green or brown deposit in the peripheral cornea is pathognomic of Wilson’s disease and resolves completely with treatment. Lens opacification is a feature of Wilson’s disease, galactosaemia, Zellwegger’s hepatocerebrorenal syndrome, neonatal adrenoleukodystrophy, and neonatal haemolytic jaundice syndrome. Prolonged use of systemic adrenocorticosteroids for immunosupression following orthotopic liver transplantation may also be complicated by cataract formation, opportunistic retinal and choroidal infections. Mucopolysaccharidoses are associated with pigmentary retinopathy and two of the sphingolipidoses manifest macular “cherry red spot”. Primary biliary cirrhosis may be associated with treatable night blindness due to malabsorption of vitamin A. Parinaud’s syndrome is seen in Niemann- Pick disease, kernicterus and Wilson’s disease. Finally, there is a rare complication of acquiring hepatitis B following corneal transplantation, and should be considered prior to transplant.⁷²

Drug Induced Liver Diseases

Drug-induced liver disease (DILD) occurs in about 25 % of patients of fulminant hepatic failure.⁷³ It accounts for 2-5% jaundice in hospitalized patients and about 10% of hepatitis in all adult patients.⁷⁴ The liver is the primary site of contact of ingested chemicals and the primary site of biotransformation, thereby making it especially vulnerable to chemical injury. The factors that affect vulnerability are related to the conversion of these ingested agents to a hepatotoxic metabolites.⁷⁴ It is multifaceted phenomenon and sometimes liver disease maybe the only clinical manifestation of the adverse drug effect with or without involvement of other organs. It may occur either as an idiosyncratic reaction to the drug (sulfonamides, dapsone, sulindac, etc.) or a consequence of intrinsic toxicity of the drug (acetaminophen, inorganic iron, anabolic steroids, tetracyclines, etc.).^75,76 Clinical features most commonly include fever, eosinophilia and rash. Sometimes also have lymph node enlargement with atypical circulating lymphocytes (psuedomononucleosis).⁷⁶

CONCLUSION

Liver diseases represent an emerging health issue due to its increasing prevalence and complications worldwide. It is important for clinicians to be aware of the impact of liver diseases on the various organ systems to be able to identify the underlying liver disease early to prevent long term complications and improve the quality of life in these patients.

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Gastrointestinal Motility And Functional Bowel Disorders, Series #15

Hypertrophic Pyloric Stenosis in Adults: A Rare Entity

March 2016 • Volume XL, Issue 3

Arleen Ortiz,

Carlos Garcia-Blanco,

Brian R. Davis,

Richard W. McCallum

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The adult form of idiopathic hypertrophic pyloric stenosis (IHPS) is a rare entity with very few cases reported. Here we report a case of IHPS in an adult and review the diagnosis and management approaches as well as the latest advances in treatment approaches and future directions.

Idiopathic hypertrophic pyloric stenosis (IHPS) is predominantly a disease of infants with an incidence between 0.1% and 0.8%.1 The adult form is a rare entity with very few cases reported. We present a 34-year-old woman with Autism and Tourette’s syndrome who presented to our Tertiary center with a chief complaint for 2 years of progressive post-pandrial nausea and vomiting of undigested food. She was found to have stenosis of the pylorus on upper endoscopy examination with failure to have a sustained response to pyloric dilation treatment on two different occasions upon follow up (FU). Robotic-assisted laparoscopy pyloroplasty was performed successfully achieving resolution of symptoms over a 6 month FU. We report a case of IHPS in an adult and review the diagnosis and management approaches as well as the latest advances in treatment approaches and future directions.

Arleen Ortiz, MD PGY-5, Gastroenterology Fellow Carlos Garcia-Blanco, MD, PGY-1, Internal Medicine Resident Brian R. Davis, MD, FACS, FASGE, Program Director of Surgery Department Richard W. McCallum, MD, FACP, FRACP, FACG, AGAF, Associate Professor of Gastroenterology Department, Texas Tech Health Science Center, El Paso, TX

INTRODUCTION

Idiopathic hypertrophic pyloric stenosis (IHPS) is usually diagnosed and treated during the first few months of life. The adult form of IHPS is a rare entity and most physicians nowadays are not aware of it. This disease was first described in 1922 by Oliver a surgeon from Ohio in the Annals of Surgery.² We report a case of IHPS in an adult and then we review the experience in the literature, diagnosis and management approaches.

Case Presentation

A 34-year-old woman with Autism and Tourette’s syndrome presented with a chief complaint for 2 years of progressive post-prandial nausea and vomiting of undigested food accompanied by mild diarrhea. Her parents described that mainly solids are regurgitated and sometimes this can be food ingested from a few

days before. The patient had previously been evaluated for gastroparesis versus gastric outlet obstruction by another gastroenterologist in the community prior to referral to our Tertiary Gastroenterology Center. Prior endoscopy 4 months ago at another hospital showed pyloric stenosis and a balloon dilation with 12 mm balloon catheter was performed. Parents reported improvement of symptoms but only for a short period of approximately 1 month. Pertinent past history was Helicobacter pylori infection 2 years ago with no ulcers present and treated with an antibiotic regimen. A 20 to 30 pounds weight loss is reported within the 2 years of symptoms. Laboratory data were reviewed and the relevant findings were TSH of 2.5, HgA1c 5.7, Hg 13.5 and albumin 4.1. A Gastric emptying study (GES) was done and there was a retention percentage at 4 hours of 85%( normal <10%). Upper GI series showed significantly delayed emptying of contrast from a somewhat dilated stomach into the small bowel with no masses or ulcers apparent. (See Figure 1) A repeat Upper endoscopy was performed at our center. Pyloric stenosis was encountered with nodular and congested pre-pyloric mucosal inflammation present and smooth narrowing of the pylorus with stenosis and no masses, ulcers or extrinsic deformity identified. (See Figure 2) Biopsies were taken. A Through the Scope (TTS) balloon dilation was performed at 15 mm, 16mm, and 18 mm maximal dilation. After dilatation the pylorus was traversed and some nodular mucosa of the proximal duodenum was seen and biopsied. Pathology results of gastric tissue showed Helicobacter pylori negative chronic active gastritis and the duodenal pathology showed acute duodenitis with preserved villious architecture and no eosinophils identified. However interestingly it was noted in the prepyloric biopsy there was extensive intestinal metaplasia likely reflecting her prior history of H. pylori infection/PUD.( see Figure 3) Some eosinophils were identified in the antral mucosa biopsy, however no eosinophils were seen in the duodenum and the patient’s eosinophils blood level was normal not supporting the diagnosis of Eosinophilic gastroenteritis.

Two months after the pyloric dilation due to persistence of symptoms patient was referred for surgical evaluation and a Robotic-assisted laparoscopic pyloroplasty with the Heineke Miculicz approach was performed at our center with full thickness biopsy of pylorus and antrum. At surgery the pylorus was divided in an axial direction with extension approximately 2 cm on the stomach and duodenum. This incision was then closed in a transverse fashion with an inner layer of running suture with full thickness mucosal to serosal bites. The second layer was created with interrupted Lembert stiches (See Figure 4). Pathology specimens from surgery confirmed hypertrophic fibroadipose tissue in the pylorus consistent with the diagnosis of Idiopathic Hypertrophic Pyloric Stenosis. Pathology of the antrum of the stomach showed normal numbers of interstitial cells of Cajal (ICC) were present based on c-kit staining. There was an average of 12 ICC per high power field which is normal. Also there was a normal population of enteric neurons. There was no inflammation, necrosis, fibrosis or evidence of malignancy identified in the muscularis propia ruling out GIST and neoplastic processes. The patient responded well to surgery, regaining weight slowly and symptoms including nausea/vomiting and diarrhea have completely resolved during last follow up 6 months after surgical intervention. The family and patient report being very satisfied with the results.

We will now focus on the discussion and review of literature for adult Idiopathic hypertrophic Pyloric Stenosis, a rare entity but important diagnosis of exclusion for investigating the explanation of nausea and vomiting.

Discussion

Pyloric stenosis in the adult is classified as primary and secondary. The most common type is secondary and the main focus is scaring and distortion of distal pre-pyloric antrum and pylorus due to active peptic ulcer and accompanying scarring from healed ulcers. Zollinger-Ellison syndrome as a rare cause of recurrent peptic ulcer disease should always be considered and the serum gastrin level in our case was normal. Hypertrophic gastritis (Ménétrier’s disease), adenocarcinoma, gastrointestinal stromal tumors, carcinoid tumors, lymphomas including MALT, eosinophilic gastroenteritis, bezoars and extrinsic effects of postoperative adhesions or ectopic pancreas tissue are in the differential diagnoses and were excluded in our patient.^1,3-5 No malignancies were identified on imaging or pathology. No ulcers were identified on endoscopy and mechanical obstruction secondary to food or external lesion/adhesions was not identified on imaging or endoscopic examination. The history of previous peptic ulcer disease and the extensive histological metaplasia in the antrum was assumedly due to past Helicobacter pylori infection. This was not associated with active ulcers or pyloric scarring.

Development of HPS without obvious predisposing factors is defined as primary or Idiopathic. This type is characterized mainly by hypertrophy and hyperplasia of the pyloric muscle with evidence of hypertrophied fibroadipose tissue in the pathology sample.^6,7 This entity is mainly described in the first few weeks and months of life typically in the first born male child with a higher prevalence in the Jewish population. The adult type is extremely rare with only about 200 cases described in the literature.^1,5 For unknown reasons Idiopathic HPS seems to be more prevalent in middle-aged males (80%),^9-11 although our case is in a female, and there are reports of middle-aged female presentations.⁷

The etiology remains uncertain. Genetic factors have been proposed and a familial form of HPS has been described. ¹²Some authors have hypothesized that Adult IHPS is a persistence of the milder form of infantile IHPS, since anatomical and histological changes are similar.^13,14 This theory implies that there is a relatively asymptomatic phase for some years until inflammation, edema or spasm precipitate occlusion of the pylorus triggering symptoms. In our patient her mental state challenges with Tourette’s syndrome and Autism clearly limited understanding from her history whether some symptoms may have been present over the years.

Clinical presentation in the adult is similar to gastric outlet obstruction with symptoms including epigastric pain, nausea, vomiting, and early satiety. In children an “olive” sized abdominal mass may be palpated in the right upper quadrant but has not been reported in adults. Imaging examination does not provide pathognomonic findings; but excludes neoplasm and extrinsic masses. Upper GI series will typically show barium stopping at the pylorus and can define a smooth symmetric appearance of pylorus while ruling out bezoars, ulcers, masses and other disease.¹⁵ Abdominal CT scan can be helpful by showing distal stomach thickening and perhaps dilatation of proximal stomach.¹⁵ Upper endoscopic (EGD) examination is required to rule out peptic ulcers and neoplastic processes plus obtaining biopsy tissue for other possible etiologies as performed in our case. Pyloric biopsies are important as there is a case of GI stromal tumor or a spindle cell neoplasm presenting as IHPS in the literature. Our pyloric surgical tissue also excluded this possibility.⁸ On EGD examination the pylorus has a fixed appearance with smooth borders previously described by Schuster and Smith as the “cervix sign”.¹⁶ Definitive diagnosis is done by pathology of the surgical specimen. Typical microscopic findings include hypertrophy and hyperplasia of inner circular muscle layer of the pylorus.^6,17,18 Gross examination seen mainly by surgeons at the time of surgery includes an elongated and thickened pylorus. The normal defined thickness of the pylorus muscle is 3 to 8 mm with an average of 4 mm.^11,19 In adult hypertrophic pyloric stenosis the thickness is increased to as much as 1 to 1.5 cm on average and measurements as high as 3 cm have been reported in the literature.⁹

The treatment for IHPS is surgery. A possible correlation with long-term hypertrophic pylorus and the development of gastric carcinoma has been reported.⁵ An older surgical approach is gastric resection and Billroth I anastomosis. The current recommendation is pyloroplasty, either open or laparoscopic. The less invasive surgical approach of laparoscopic pyloroplasty has become the procedure of choice by most surgeons as it is highly effective and safe.²⁰ A further advancement is robotic-assisted laparoscopic pyloroplasty which was performed in our patient. The Heineke Miculicz surgical pyloroplasty technique entails dividing the pylorus in an axial direction with extension approximately 2 cm on the stomach and duodenum. This incision is then closed in a transverse fashion with an inner layer of running suture with full thickness mucosal to serosal bites. The second layer is created with interrupted Lembert stiches (See Figure 4).

Other proposed therapeutic interventions include aggressive dilation of pyloric stenosis, an acceptable treatment which has a high recurrence rate only providing temporary relief.^21-24 Intra-pyloric injection of botulin toxin into the muscle layer to relax the muscle is another approach. This is not a definitive treatment but may provide brief improvement as described in infantile hypertrophic pyloric stenosis.^25,26 Upon literature review a recent publication proposed a partially covered self- expandable metallic stents as a safe and favorable outcome in the treatment of benign pyloric obstruction and in salvage after balloon dilation failure. ²⁷ The authors report an overall rate of 90% being symptom free at a median of 11 months follow-up with no serious adverse events reported after stent placement.²⁷ It would be assumed that stent dislodgement would occur over time.²⁸

New improvements in flexible endoscopic instrumentation are allowing for a less invasive endoscopic pyloromyotomy approach. A recent report in the Journal of GI Endoscopy showed results of treatment in four pigs with submucosal dissection of the circular muscle layer achieving a successful pyloromyotomy.²⁸ Endoscopic pyloromyotomy has been successfully described in the literature as early as 2005 in 10 patients with congenital pyloric stenosis with no complications and 100% success rate.²⁹ The same authors propose this technique as an equally effective modality as laparoscopic pyloroplasty.²⁹ There is also a case report of gastric peroral endoscopic myotomy in a young woman with refractory gastroparesis who underwent endoscopic pyloromyotomy with a triangular-tip knife (KD 640L; Olympus) and submucosal dissection technique cutting into muscularis propia extending from the pylorus sphincter to 0.5 cm into duodenal bulb.³⁰ The patient tolerated the procedure without complications and 12 weeks post procedure follow up showed significant improvement of gastroparesis symptoms.³⁰ This technique of endoscopic pyloromyotomy raises the possibility that in the near future this can be an alternative to surgery for both Pediatrics and Adult hypertrophic pyloric stenosis treatment.

Take Home Message

The entity of idiopathic hypertrophic pyloric stenosis in an adult should be considered when patients present with nausea and vomiting which has not responded to empiric attempts to control symptoms with antiemetics and proton pump inhibitors to address the accompanying heartburn from vomiting gastric acid. The vomiting profile may suggest gastroparesis in that contents are vomited some hours after eating and food from previous meals may be recognized. Weight loss may also become a concern. Gastroenterologist should be sensitized by our review that there is the entity of adult idiopathic hypertrophic pyloric stenosis and that there is a surgical solution, currently best achieved by laparoscopic pyloroplasty with robotic assistance.

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A Case Report

Attenuated Familial Adenomatous Polyposis: A Novel Treatment with Celecoxib

February 2016 • Volume XL, Issue 2

Zachary S. Neubert,Mark Potter

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Zachary S. Neubert, DO, Madigan Army Medical Center Internal Medicine Mark Potter, DO Associate Professor, Department of Gastroenterology, Department of Medicine, Madigan Army Medical Center, Tacoma, WA

INTRODUCTION

Attenuated familial adenomatous polyposis is characterized by multiple adenomatous polyps that develop later in life and prompt close screening due to a high propensity of malignant transformation. The usual curative treatment is surgical resection.³ This case describes the use of alternative medical therapy with COX-II inhibitors with near complete resolution of polyps.

Case Report

A 53-year-old African American male underwent a screening colonoscopy which revealed numerous polyps ranging in size from diminutive to large (Figure 1). His past medical history was significant for hypertension, insulin dependent diabetes, and hyperlipidemia. He had no known family history of colon cancer. Polyps were removed and found to be tubular adenomas.

Repeat colonoscopy 6 months later demonstrated more than 50 polyps with a right sided distribution; roughly 20 were removed and all again were found to be tubular adenomas. The patient was then sent for genetic testing which revealed attenuated familial adenomatous polyposis. Patient was referred to surgery, opted for a right hemicolectomy with continued surveillance instead of a subtotal colectomy. After a successful right hemicolectomy, surveillance colonoscopy revealed multiple more small to medium sized polyps (> 20) in the remaining colon.

Once again the patient decided to forgo a subtotal colectomy and opted instead to start chemoprevention, celecoxib 400mg twice daily with continued interval surveillance. After 6 months of medical therapy surveillance colonoscopy showed that his polyp burden dramatically decreased. Only one small tubular adenoma was found.

Discussion

Attenuated FAP is a milder variation of FAP, characterized by an average age of 44 at presentation, oligopolyposis (less than 100 polyps), and with a right colonic distribution.^2,3 There still exists nearly 100% incidence of colorectal cancer with these patients, averaging roughly 10-15 years past time of initial presentation and care must be taken to continue aggressive surveillance of disease burden. Attenuated FAP is characterized by MUTYH base-excision repair mutation without loss of the APC gene. There is a higher incidence of extra-colonic adenomatous polyps in patients who had prophylactic colectomies, including gastric fundus polyps and periampullary carcinoma, of which the latter is the major cause of death in these patients.² Thus it is imperative to continue ongoing gastrointestinal surveillance in these patients.

In 2001, FDA approved the use of COX-II inhibitors for chemoprophylaxis in patients with Familial Adenomatous Polyposis (FAP) due to several randomized clinical trials showing significant tumor reduction.⁵ Use of COX-II inhibitors for attenuated FAP has been described in the literature only as a single case report with nine year follow-up as potential chemo preventative strategy with ongoing surveillance in lieu of surgical resection.⁶ Clinical trials currently underway are targeted at inhibiting the EGFR receptor which may cause reduced proliferation of polyps. It is still unclear whether reduction of polyps early in the disease process offers protection against malignant transformation later in life. If celecoxib becomes efficacious for this disease, it could offer patients an alternative non-surgical therapy which may reduce morbidity associated with colonic resection but would necessitate ongoing GI surveillance. It may bring about more risks involved in patients with multiple comorbidities given the FDA black box warning of increased incidence of gastrointestinal bleeding with use of NSAIDs as well as the adverse cardiovascular effects of MI and stroke.

To our knowledge, this is only the second case showing polyp eradication with use of celecoxib in patients with aFAP. This treatment for aFAP may be a novel non-surgical approach to this disease, and should be further investigated.

Disclaimer: The views expressed are those of the authors and do not reflect the official policy of the Department of the Army, the Department of Defense or the United States Government.

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Frontiers In Endoscopy, Series # 25

Removal of Migrated Pancreatic and Biliary Stents: Techniques and Outcomes

February 2016 • Volume XL, Issue 2

Robert Mitchell,

Douglas G. Adler

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Biliary and pancreatic stents are primarily used for the treatment of benign and malignant strictures of the biliary tract and pancreatic duct, among other indications. A recognized complication of the use of these stents is migration, which can be source of significant morbidity and mortality. Although distal migration is more common, proximally migrated stents can be challenging to retrieve and can create clinical problems for patients. The purpose of this article is to review current literature regarding migration of pancreatic and biliary stents, particularly proximal migration, and the techniques used to retrieve them.

Robert Mitchell MD and Douglas G. Adler MD, FACG, AGAF, FASGE, University of Utah School of Medicine, Gastroenterology and Hepatology, Huntsman Cancer Center, Salt Lake City, UT

INTRODUCTION

Incidence of Proximally Migrated Stents

The incidence of proximal stent migration can be evaluated by location and type of stent. For plastic biliary stents, a 1992 study found that of 322 plastic biliary stents placed in the common bile duct 16 (4.9%) migrated proximally. Half of those patients were symptomatic at presentation. Factors that were associated with proximal migration in this study included larger stent diameter (odds ratio 4.5), a stent length less than 7 cm (odds ratio 7.8), and a malignant stricture secondary to cholangiocarcinoma (odds ratio of 5.2).¹ A more recent study published in 2008 reported that in a group of 524 patients undergoing biliary stent placement, 24 plastic biliary stents migrated proximally (4.6%).² One of 43 fully covered metal stents (2.3%) migrated proximally in this study.³ For uncovered metal stents, the proximal migration rate is quite low and usually less than 1%, attributed to the stent fixation by tumor ingrowth.⁴

For pancreatic stents, the same 1992 study included 267 patients that had pancreatic stents placed with 14 of those migrating proximally (5.2%). Factors associated with proximal pancreatic stent migration were a diagnosis of sphincter of Oddi dysfunction (odds ratio 4.2) and stent length greater than 7 cm (odds ratio 3.2).¹

Complications of Proximally Migrated Biliary Stents

Many patients with proximal biliary stent migration may present asymptomatically and are discovered at stent exchange, although patients can also present with a variety of symptoms including pain, jaundice, ductal obstruction, and cholangitis. In a 1995 study, cholangitis occurred in 4 out of 27 cases with benign strictures and 5 out of 17 cases with malignant strictures. ⁵ The time to presentation for cholangitis varies with one patient presenting as early as 4 days and another presenting as far as 6 weeks from placement. ^5,6 Ductal obstruction typically occurs with rates of 2% to 21% of stent migration.2,5 The time to presentation with ductal obstruction can occur as far out as 3 months since placement.⁷ As many as 50-87.5% of patients with proximally migrated biliary stents can present without symptoms. The median time interval of presentation with proximal migration was 5 months.^1,8-9

Complications of Proximally Migrated Pancreatic Stents

Like biliary stents, many patients with proximal pancreatic stent migrationmay present asymptomatically and can be discovered at stent exchange, but many other present with abdominal pain due to or unrelated to pancreatitis. Some of the recognized complications of proximally migrated pancreatic stents include pancreatitis, stent occlusion, morphologic changes of the pancreatic duct, and stent fracture.¹⁰ In a study looking at 9 patients with proximally migrated pancreatic stents, 3 patients presented with pancreatitis (33%). The other 6 patients (67%) presented without symptoms at stent exchange.9 Although there have been no studies looking at rate of ductal injury following migration, pancreatic stents are known to cause ductal changes including ductal irregularities, narrowing, and parenchymal changes.¹¹ The median time interval from stent placement until stent migration was diagnosed was 2.3 months.⁹

Retrieval Techniques

The retrieval of both pancreatic and biliary stents can be categorized as follows: direct traction on the stent, indirect traction on the stent, and retrieval after cannulating the duct, often involving cannulation of the stent lumen at the same time. Direct traction involves grasping the stent directly with a basket, forceps, snare, or a sphincterotome and pulling the stent out of the duct. (Figures 1-8) Indirect traction is performed with inflating a balloon above or alongside the migrated stent and then pulling the balloon towards the distal duct in an attempt to move the distal end of the stent into the duodenal lumen. Retrieval after cannulating the stent lumen usually involves cannulation with a guidewire and then using a variety of over-the-wire accessories to retrieve the stent. These accessories include Soehendra stent extractor, basket, occlusion balloon, dilation balloon, forceps, or a sphincterotome.⁹

Plastic Biliary Stents

A 1995 study reviewed the success rate of the available retrieval techniques for proximally migrated plastic biliary stents. The study included 44 cases of proximal migration. Twenty-seven of the forty-four proximally migrated plastic stents were placed for benign strictures while seventeen were used to treat malignant strictures. Of the methods used, cannulation and retrieval with a Soehendra stent extractor was the most common with thirteen of the thirty-six successful retrievals (36%). Other stent cannulation techniques used successfully were basket in two patients, forceps in one patient, dilation balloon in one patient, and a sphincterotome in which the distal flap of the stent was entrapped by the cautery wire in one patient. The second most successful technique was with indirect traction with a stone extraction balloon with seven successful extractions (19%). Direct traction was also successful technique with five stents removed directly with a basket (14%), five removed directly with forceps (14%), and one removed directly with a sphincterotome (3%). The authors reported an overall success rate of 82% with most of the irretrievable stents occurring in patients with malignant strictures.⁸

In a 1999 retrospective study at a tertiary center reviewed forty-six patients with proximally migrated biliary stents, the most successful technique was with direct traction with a basket with twenty-two successful retrievals (59%). The second most successful technique was with a balloon with 4 successful retrievals (11%). However, the study did not differentiate between indirect traction and stent cannulation and what type of balloon that was used. Direct traction with forceps was used in three patients (8%). Direct cannulation with a Soehendra stent retriever was successful in 2 patients (5%). They also used a combination of indirect traction with a balloon and direct traction with a basket that was successful in three patients (8%). They also used a combination of basket and ball tip catheter that was successful in 2 patients (5%). They reported a success rate of 90%. The four stents that were irretrievable were associated with malignant strictures.¹²

A 1998 retrospective study at a tertiary center reviewed 33 cases of proximally migrated biliary stents. Eighteen of the cases were with benign strictures and fifteen with malignant strictures. The most commonly used technique for stent retrieval in patients with benign strictures was direct traction with ten successful retrievals. Of the ten cases, six used a basket, two used forceps, and two used a snare. Three of the benign stricture cases were successful with indirect traction with a stone extraction balloon. As for stent cannulation techniques, two cases were successful with a stone extraction balloon and one case with a Soehendra stent extractor. In patients with proximally migrated stents above with malignant strictures, the most used technique was stent cannulation with six of the fifteen cases. Of the six successful stent cannulation techniques, three were with a stone extraction balloon and three were with a Soehendra stent extractor. With direct traction techniques, five of the fifteen stents were retrieved with four being retrieved with a basket and one with a snare. Indirect traction with a balloon was not successful in patients with proximally migrated stents above malignant strictures. Of the migrated stents in patients with benign strictures, sixteen of the eighteen stents were able to be retrieved (89%). Two patients were lost to follow up. Of the migrated stents associated with malignant strictures, twelve of the fifteen stents were able to be retrieved (80%). Three were not able to be retrieved and a second stent was placed to allow for drainage.⁹

A 2009 retrospective study at a tertiary referral center analyzed all patients that underwent biliary stent placement between December 2004 and March 2006. They identified twenty-four cases of proximal migration of plastic biliary stents out of a total of 524 patients. Half of the twenty-four migrated stents were removed with a stone extraction balloon with indirect traction. The other half were removed with direct traction with biopsy forceps. They were able to retrieve all of the proximally migrated stents endoscopically.²

Several case reports documenting novel techniques to remove proximally migrated plastic biliary stents exist. One case report used a sphincterotome advanced over a wire to beyond the proximal end of the stent. Then, the proximal end of the sphincterotome was bowed to form a hook, which caught the stent, allowing removal with traction.¹³ Another report used a cholangioscope to directly visualize the migrated stent and to allow selective cannulation of the stent itself with a guidewire followed by the stent being removed with a Soehendra stent extractor.¹⁴ Another case report demonstrated success with a combination of a basket and a guidewire to form a loop to catch the distal end of the stent.¹⁵ A comparison of the studies discussed for plastic biliary stent retrieval can be seen in Table 1.

Metal Biliary Stents

Metal biliary stents come in two categories: covered or uncovered, with covered stents being further subdivided into partially covered, fully covered, and fully covered but fenestrated. Covered stents, as the name implies, are covered in polyurethane or polyethylene to prevent tumor ingrowth. It is this covering that also increases the risk of stent migration as the metal struts cannot imbed in the bile duct wall. Uncovered stents allow for the possibility of tumor ingrowth and are, overall, much less likely to migrate. Because covered stents are more likely to migrate, there is more literature regarding fully covered stent migration and their retrieval.

A 2008 prospective study from the Netherlands evaluated the removability of fully covered self- expandable metal stents (FCSEMS) in benign common bile duct strictures. FCSEMS were placed in six patients with proximal stent migration occurring in two patients. In the first patient, they attempted retrieval with a snare, but it caused the distal end of the stent to become impacted in the common bile duct wall. They attempted dilating the stricture and expanding the papillotomy opening, but the stent could not be retrieved. Plastic stents were placed to allow for drainage. In the second patient, the stent was cannulated with a guidewire and retrieved with a dilation balloon.¹⁶

A 2011 multicenter, prospective comparative pilot study studied the anti-migration effects and complications rates of fully covered self-expandable metal stents. In forty-three patients with benign strictures, twenty-two were assigned to the anchoring flap category and twenty-one to the flared end. Both of the FCSEMS had a flared end on the distal portion of the stent, but the stents with the anchoring flaps had four flaps at the proximal end of the stent. The flared end group had proximal migration in one patient and distal migration in six patients. The proximally migrated stent was successfully removed with rat-tooth forceps under fluoroscopy.¹⁷

A 2014 case series reported on five patients with proximally migrated fully covered self-expandable metal stents and their retrieval in patients with benign strictures. In the first patient, proximal migration and distal impaction was discovered eleven months later at elective ERCP. A wire was passed alongside the stent and a dilation balloon was used to retrieve the stent. Retrieval was not successful so plastic stents were placed to allow for drainage. Two months later, the plastic stents were removed and retrieval was attempted again with a dilation balloon and failed. A FCSEMS was placed for drainage. Two months later, the FCSEMS and the migrated stent was removed simultaneously with rat- tooth forceps. The other four patients were similar with migrated stent retrieval failure with dilation balloons, forceps, and loops. All four had the a new FCSEMS placed at the distal end of the migrated stent and the two stents removed together with forceps two to six weeks later.¹⁸ This case series emphasizes some of the very real potential difficulties in removing proximally migrated SEMS. A comparison of the studies discussed can be seen in Table 2.

One case report exists describing a patient with a proximally migrated uncovered SEMS but this patient underwent attempt at stent removal, but instead placed a second stent across the biliary stricture to allow for drainage.⁴

Pancreatic Stents

Pancreatic stents are used for a variety of conditions such as pancreatic duct strictures, drainage of pancreatic pseudocysts, treatment of pancreatic duct leaks, and (most commonly) as prophylaxis against the development of post-ERCP pancreatitis. All dedicated pancreatic duct stents are currently plastic. SEMS have been used in the pancreas in a limited manner off label. Proximally migrated stents can present special challenges as the pancreas has ducts that are smaller and the pancreas is, in general, less tolerant of interventions. The pancreatic duct also has side branches with can trap the ends of a pancreatic duct stent, making retrieval potentially very difficult if the distal end of the stent cannot be accessed easily. Many of the techniques used for biliary stents are successful with retrieval of pancreatic stents.

A 2009 retrospective study reviewed thirty- three cases of proximally migrated pancreatic stents at a tertiary referral center. Of the thirty-three cases, twenty-three were placed endoscopically while ten were placed surgically.¹⁰ The most successful technique was with a dilation balloon with indirect traction with eight of the endoscopic stents (35%) and two of the surgically placed stents (20%) removed with this technique. The second most common technique was with direct traction with forceps with five of the endoscopic stents (22%) and two of the surgical stents (20%) retrieved successfully. Direct traction with a snare retrieved one endoscopic stent and one surgical stent. Stent cannulation with a guidewire followed by snare capture was successful in two of the endoscopically placed stents. Baskets were used in one endoscopic stent and two surgical stents. One of the surgical stents was removed, but it was unclear in the chart which technique was used.

One endoscopic stent required interventional radiology and a loop snare. Nine patients required multiple procedures for successful retrieval. Five stents could not be retrieved with four requiring surgical removal and one patient treated with observation. The endoscopic retrieval success rate reported was 78% in endoscopic stents and 80% in surgical stents.

A 1998 retrospective study at a tertiary center reviewed clinical findings and outcomes in twenty-six cases of proximally migrated pancreatic stents. The study distinguished between main/ventral pancreatic stents (10 cases) and dorsal pancreatic stents (16 cases).9 For the main pancreatic duct stents, eight of the ten stents were successfully retrieved (80%). The stents were retrieved using a standard wire basket in 3 patients, a mini-basket in one patient, and wire guided basket in one patient. Two of the stents were removed with indirect traction with a stone extraction balloon and one was removed with direct traction with a stone extraction balloon. Of the two that were not able to be retrieved, one required a distal pancreatectomy because of the severity of the symptoms while the other patient was observed clinically and the stent was left in situ. For the dorsal pancreatic duct migrated stents, 12/16 (75%) cases were successfully retrieved. The stents were retrieved using a basket in five patients, a stone extraction balloon providing indirect traction in 3 patients, a stone extraction balloon with direct traction in one patient, a snare in two patients, and a rat tooth forceps in one patient. In the 4 patients whose stents were not able to be retrieved, 2 were asymptomatic and were followed clinically with normal serum amylase levels after two years of follow up while the other two patients required surgical removal of the stents.

Several case reports have been published that document novel techniques to remove proximally migrated pancreatic stents. One case report attempted retrieval with snares, baskets and balloons with no success. At this point, the Spyglass (Boston Scientific, Natick MA) visualization system was used to directly evaluate the stent and revealed that the stent had migrated into a side branch of the pancreatic duct. The stent was grabbed by a miniature forceps and removed.19 Another case report used a rotatable cardiology guidewire with a 3.0 mm angioplasty balloon after failure with indirect traction with a stone extraction balloon, Soehendra stent extractor, and snare.²⁰ Another case report used a guidewire to cannulate the stent as a means to facilitate placing another stent within the distal end of the initial (migrated) stent. The two stents were removed together en bloc with forceps and a snare.²¹ Comparison of the retrieval techniques used in the studies can be seen in Table 3.

Endoscopic Failure-Indications for Surgery

Failure to retrieve a proximally migrated endoscopic stent may warrant evaluation by surgery for stent removal, especially if the patient is symptomatic. A 2009 retrospective study reviewed thirty-three cases of proximally migrated pancreatic stents at a tertiary referral center. Of the thirty-three cases, five stents were not able to be retrieved endoscopically. One was asymptomatic and was observed. Of the four patients that required surgeries, three underwent distal pancreatectomies while the fourth had a surgical revision of a remote pancreaticojejunostomy.¹⁰

In some patients attempts at stent removal, while usually successful, are contraindicated necessitating early surgical referral. A case report describes a patient that required surgical removal of a proximally migrated plastic biliary stent. Abdominal x-ray showed that the proximal end of the stent had migrated to the level of the diaphragm. CT abdomen showed that the proximal end had migrated into the inferior vena cava through the middle hepatic vein. Stent retrieval was not attempted because of the risk of uncontrolled bleeding. The stent was removed surgically and the patient underwent creation of a Roux en Y hepaticojejunostomy.²²

CONCLUSION

Retrieval of migrated biliary and pancreatic stents can be challenging, especially proximally migrated stents. Most migrated stents can be removed endoscopically without the morbidity of surgery. Although most reports used a variety of techniques, some of the more commonly used were direct traction with a snare or forceps and indirect traction with a dilation or stone extraction balloon. These techniques are often the first to be used for the removal of the stents. Some of the retrievals required multiple attempts for removal. As more novel techniques develop, retrieval rates may improve. In those that fail endoscopic retrieval, surgical removal can still be considered.

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Gastrointestinal Motility And Functional Bowel Disorders, Series #14

Intestinal Malrotation Volume II: Small Bowel Malrotation: A Perspective For The Adult Gastroenterologist

February 2016 • Volume XL, Issue 2

Richard W. McCallum,

Roy P. Liu,

Asmik Asatrian

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Small bowel malrotation is the lack of or incomplete rotation of the intestines around the axis of the superior mesenteric artery (SMA) during embriologic development. Currently computed tomography (CT) is the best imaging modality to demonstrate findings of small bowel malrotation such as inversion of the SMA and superior mesenteric vein (SMV). In symptomatic patients, Ladd’s surgery is the best treatment option. However, in asymptomatic patients management is controversial. In this article we provide a rational approach for diagnosis and summarize treatment options available.

Small bowel malrotation is the lack of or incomplete rotation of the intestines around the axis of the superior mesenteric artery (SMA) during embriologic development. Incidence of small bowel malrotation in adults is between 0.00001% and 0.19%. Most patients can present with months to years of unexplained abdominal pain, nausea or vomiting. However, 50% of adult patients with small bowel malrotation can be asymptomatic and be diagnosed incidentally from abdominal imaging studies performed for other reasons. Currently computed tomography (CT) is the best imaging modality to demonstrate findings of small bowel malrotation such as inversion of the SMA and superior mesenteric vein (SMV). In symptomatic patients, Ladd’s surgery is the best treatment option. However, in asymptomatic patients management is controversial. Some prefer surgical intervention to prevent life-treatening complications; others argue that the risks of surgery outweigh the benefits in the setting where patients have lived their lives without complications.

Richard W. McCallum, MD, FACP, FRACP (AUST), FACG, AGAF Professor and Founding Chair Department of Medicine, Director Center for Neurogastroenterology/GI Motility Roy P. Liu, MD, PGY-5, Fellow Physician Asmik Asatrian, MD, PGY-1, Resident Physician El Paso TX

INTRODUCTION

Small bowel malrotation is a congenital anomaly due to either lack of or incomplete rotation of the fetal intestines around the axis of the superior mesenteric artery during fetal development. More specifically, the duodenum courses down the right side of the abdomen, the ligament of Treitz fails to cross the midline to the left side, and the cecum remains attached to the right side of abdominal wall through peritoneal fibrous bands known as Ladd’s bands (Figure 1). Ladd’s bands can form and extend from the right colon, across the duodenum, to the right lateral abdominal wall and entrap the descending duodenum causing intermittent obstruction.^1,2 Other congenital rotational disorders of the small intestine include nonrotation and reversed rotation. In nonrotation, there is complete failure of the midgut to rotate around the superior mesenteric artery leading to the duodenojejunal junction being displaced to the right side of the abdomen and the ileum entering the cecum from the right side, with the large bowel located in the left abdomen¹ (Figure 2).

Nonrotation is generally discovered in adulthood and is more commonly an incidental finding on imaging or during surgery.³ Reversed rotation is an abnormal clockwise rotation of the midgut by approximately 90 degrees wherein the transverse colon lies to the right of the superior mesenteric artery and passes through a retroduodenal tunnel dorsal to the artery in the small intestinal mesentery (Figure 3). It is associated with the cecum and the colon being poorly fixed which can lead to torsion.⁴ Malfixation can also occur where there is only a small vertical attachment of the small bowel mesentery resulting in limited fixation to the retroperitoneum. This makes the small bowel highly mobile and prone to midgut volvulus.²

Roughly 64-80% of patients with malrotation present with bilious vomiting in the first month of life due to duodenal obstruction or a volvulus.^6,7 This is reviewed in the companion article addressing the pediatric perspective. In adults, malrotation can manifest with symptoms ranging from acute abdomen, intestinal obstruction, unexplained abdominal pain, nausea and vomiting and more likely as an incidental finding in otherwise asymptomatic patients. Due to the variable presentation and rarity of this condition in adulthood, the proper management and role for operative intervention in these patients remain controversial.¹ For instance, Ladd’s procedure, which involves counterclockwise reduction of volvulus, division of coloduodenal bands, widening of mesenteric base to prevent repeated volvulus and prophylactic appendectomy, has been shown to provide similar benefits in adults as it does in children. However, in adults this experience is not extensive and clinical presentation does not exactly parallel that observed in children.^10,11

Epidemiology

In adults, there is a slight female predominance.¹ In the pediatric literature, the impression is that up to 80% of patients with malrotation are diagnosed in the first month and 90% of these are diagnosed within the first year of life.⁸ However, in a study of 170 patients of both pediatric and adult ages who did receive the diagnosis of malrotation, 48% were > 18 years old demonstrating that adults could be affected as well.¹

Clinical Presentation

Most patients present with poorly characterized abdominal pain, unexplained nausea and vomiting.1 They can also present with diarrhea, early satiety, bloating, dyspepsia, abdominal swelling, palpable abdominal mass or melena.^13,14 Many of them have these symptoms for months to years and are diagnosed with small bowel malrotation when a CT scan was performed as part of the work up.¹ However, up to half of adult patients with malrotation can be asymptomatic.³ Complications of malrotation in adults include intestinal obstruction, acute abdomen, and volvulus of the midgut or ileocecum.¹ There have also been reports of malabsorption, peritonitis and septic shock.¹⁵ Due to the rarity of this disease in adults, it can be misdiagnosed as irritable bowel syndrome, peptic ulcer disease, acute appendicitis, cholecystitis, enteritis, left colonic diverticulitis, biliary and pancreatic disease and psychiatric disorders before the correct diagnosis is finally made.^14,16,17

Diagnosis

Historically, patients with suspected midgut volvulus would undergo barium enema to evaluate cecal position.⁴ In the 1960s, upper gastrointestinal (UGI) and small bowel contrast series became the gold standard for evaluation of suspected malrotation in a child since it allows for visualization of the duodenojejunal junction and has an accuracy of approximately 80%.^15,18 Malrotation can manifest as a right sided duodenojejunal junction or proximal jejunal loops on the right side on UGI series.¹⁵ Conventional plain radiography is neither sensitive nor specific for malrotation although right-sided jejunal markings and the absence of a stool-filled colon in the right lower quadrant may be suggestive.¹⁶ Abdominal doppler ultrasound may show malposition of the SMA with or without abnormal location of the hollow viscus.⁵ Recently CT has become more popular due to its ability to better illustrate the findings predictive of malrotation, such as inversion of the SMA and SMV, as well as bowel position, viability and volvulus.¹⁹ In malrotation, the SMV is often located to the left of the SMA or rotates around it.²⁰ Indeed, in a study of 170 patients with malrotation of whom 82 were adults, 61% of them were diagnosed by CT.¹ It is important to note, however, that some patients with malrotation will have a normal SMA/SMV relationship and an inverted relationship can also be seen in patients without malrotation.²¹ Therefore, isolated detection of such an abnormality is not sufficient for diagnosis but should warrant closer examination of the bowel. On angiography, the appearance of the “barber pole sign” is suggestive of malrotation if there is volvulus of the entire small bowel with twisting of the SMA and SMV²² (Figure 4).

Midgut volvulus is a complication of malrotation in which clockwise twisting of the bowel around the SMA axis occurs because of the narrowed mesenteric attachment.⁵ It can manifest as a corkscrew appearance on UGI series.¹⁶ CT can show a whirlpool sign in which the bowel and mesentery twist around the axis of the SMA creating a swirling appearance.^24,25 Other radiographic findings include duodenal obstruction, congestion of mesenteric vasculature, and malpositioned duodenum and cecum from the underlying malrotation.⁵ However, there are no reliable means of predicting which group of patients with intestinal malrotation will develop complications such as midgut volvulus.¹¹

Internal hernia due to abnormal peritoneal bands is another complication which may be life-threatening because of possible bowel obstruction and strangulation. It can manifest as malrotation with small bowel obstruction (without volvulus) on CT.⁵

Treatment

In patients with symptomatic malrotation, the established treatment is Ladd’s procedure to improve symptoms and reduce the risk of future complications such as volvulus and bowel ischemia.¹ The urgency of the intervention depends on symptoms at presentation.⁹ In a study of 170 patients with malrotation of whom 82 were adults, approximately 60% of these patients underwent surgery and 50% of them had resolution of their symptoms post-operation.¹ Of the patients who underwent surgery, only 35% had Ladd’s procedure.¹ However, the management of the asymptomatic patients with incidentally discovered malrotation is controversial. While some authors recommended patient education and avoidance of operation unless symptoms or complications arise,⁸ others have argued that the risk of midgut volvulus warrants surgical intervention regardless of age in all operative candidates.^26,27 Surgical intervention in asymptomatic patients in the form of the Ladd’s procedure as described can also eliminate the possiblity of ongoing morphological progression thereby decreasing the future risk of volvulus. ²⁸

Discussion

Intestinal malrotation is any deviation from the normal 270 counterclockwise rotation of the midgut during embryologic development.¹⁶ It was first described through embriology by Dott in 1923²⁹ and then later in 1936 Dr. William Ladd, an American pediatric surgeon from Massachusetts, wrote an article detailing the surgical treatment of intestinal malrotation that now bears his name.¹⁰ This procedure, also known as “Ladd’s procedure”, involves counterclockwise detorsion of the bowel, division of bands crossing from the cecum to the lateral peritoneal gutter, and widening of the mesenteric base with positioning of the colon in the left abdomen and the small bowel in the right abdomen. The appendix is removed to prevent a future diagnostic dilemma because the cecum is not in its usual location in the right lower quadrant.³⁰ According to Nehra et al, the majority of patients under the age of 18 with malrotation underwent Ladd’s procedure but only 35% of adults had a Ladd’s procedure. The reasons for this difference include increased operative risk, less familiarity in management of malrotation among adult general surgeons compared with pediatric surgeons, and other adult surgical issues including adhesions and anatomical changes from previous surgeries.¹ That being said, operative management may be the more prudent treatment plan for asymptomatic patients with malrotation given the risk of volvulus unless there is significant operative risk related to comorbid conditions.¹ Midgut volvulus may arise as follows: the malrotation and abnormal cecal location can produce a narrow superior mesenteric vascular pedicle and this narrow SMA takeoff, in combination with a lack of posterior peritoneal fusion, predisposes patient to midgut volvulus and obstruction.¹¹

Laparoscopically performed Ladd’s surgery, which is better and safer than a laparotomy, could be preferable where adults have only mild symptoms.²⁸ In a study of 7 adult patients who underwent laparoscopic treatment of intestinal malrotation, it was concluded that laparoscopic Ladd’s procedure is an acceptable alternative to open technique with high degree of patient satisfaction in relieving symptoms of intestinal malrotation.¹⁰

Interestingly, there have also been case reports of small bowel malrotation even in elderly patients. An 85 year-old male with acute abdomen underwent surgery and was found to have malrotation complicated by volvulus intra-operatively. Postoperative course was complicated with compartment syndrome and pneumonia which resulted in 2 additional laparatomies and eventually to the death of the patient on 48th postoperative day.² This emphasizes the importance of considering small bowel malrotaion in the differential diagnosis of unexplained abdominal pain in any age groups and perhaps with a low threshold to perform earlier surgical intervention in patients who are otherwise asymptomatic or with mild symptoms due to potential life-threatening complications later on in the disease course. However, in patients with a working diagnosis of IBS, peptic ulcer disease, functional dyspepsia, intestinal adhesions, the possibility that malrotation has been missed and could explain their symptoms needs to be considered.

On the other hand, in patients with an established diagnosis of irritable bowel syndrome (IBS), or nausea and vomiting attributed to gastroparesis, or abdominal pain attributed to adhesions from prior surgeries, or peptic ulcer disease, or even severe constipation there can be the incidental finding of small bowel malrotation during imaging. The risk of surgery may outweigh the benefits of prophylactic Ladd’s procedure given the fact that these patients have lived into adulthood without complications from small bowel malrotation. This is an ongoing dilemma for the adult gastroenterologist, namely when to even consider intervening if the malrotation was found incidentally on a CT imaging performed for other indications. For instance, in a study of 177 patients over a 35 year period it was found that asymptomatic patients had a low risk of intestinal volvulus, and as such elective surgery was not recommended.³¹ It is also impossible to predict which patients will develop life-threatening complications.⁷ Therefore, further long term observational studies are needed to determine which subset of patients with otherwise asymptomatic small bowel malrotation are at high risk for complications and warrant prophylactic Ladd’s procedure.

CLINICAL PEARLS

When does the adult gastroenterologist even consider ruling out malrotation in his patients; 1) If the patient gives a history of pediatric surgery(ies) of unclear or forgotten indications. 2) Surgery for an acute abdominal problem at a young age never fully clarified for the patient, such as suspected internal hernias, volvulus, or aberrantly located appendix; 3) Where abdominal pain, nausea, or vomiting are out of proportion to objective data by standard or routine testing and where treatment approaches have been suboptimal.

We hope that our review has planted a seed for your appreciation of the spectrum of small bowel malrotation in adults. We have attempted to provide a rational approach for the diagnosis and summarized the treatment options available for these patients.

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Gastrointestinal Motility And Functional Bowel Disorders, Series #14

Intestinal Malrotation Volume I: The Pediatric Perspective

February 2016 • Volume XL, Issue 2

Eduardo D. Rosas-Blum,

Aldo Maspons

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In this article we discuss the following questions: Are there asymptomatic patients that should be screened for malrotation? If malrotation is found, what should the next step be? Should an elective Ladd’s procedure be performed or should observation be instituted?

Eduardo D. Rosas-Blum¹ Aldo Maspons¹ Paul L. Foster School of Medicine, Texas Tech University Health Science Center at El Paso,Department of Pediatric, Division of Gastroenterology, Hepatology, and Nutrition¹ El Paso, TX

Intestinal malrotation is a rare congenital abnormality that occurs when the normal rotation and fixation of the intestines does not occur.¹ About 90% of the cases of malrotation are diagnosed before the first birthday with the majority of the diagnosis being made in the first month of life.² The most common complication of intestinal malrotation is midgut volvulus which could lead to intestinal necrosis and be potentially fatal if not promptly diagnosed and surgically treated.³ The reported incidence for malrotation is estimated at 1/6,000 live births1 while the absolute incidence is unknown. Autopsy studies have reported an incidence as high as 1 % of the total population.²

The spectrum of intestinal malrotation includes non-rotation, incomplete rotation, reversed rotation, and mesocolic hernia. Non-rotation is characterized by incomplete counterclockwise rotation of the midgut around the superior mesenteric artery (SMA). Essentially the small bowel is on the left of the abdomen, the colon on the right, and the cecum displaced anteriorly and midline. This type of malrotation has an increased risk for midgut volvulus. Incomplete rotation occurs when the intestine only rotates 180 degrees rather than the total 270 degrees. The duodenojejunal junction is on the right and the cecum is in the upper abdomen just left of the SMA; the same risk of midgut volvulus is present. Reversed rotation and mesocolic hernia are rare and difficult to diagnose. Both conditions can present with chronic abdominal symptoms or acute bowel obstruction in the absence of previous abdominal surgeries.⁴

Most of the patients have an asymptomatic malrotation which sometimes is incidentally found while testing, specifically imaging for other clinical conditions. Symptomatic malrotation usually present early in life with bilious emesis and abdominal pain as the most common symptoms. Other symptoms may include hematemesis and rectal bleeding. Older children with symptomatic malrotation have more vague symptoms that include: anorexia or nausea, intermittent apnea, failure to thrive, constipation, and diarrhea.³ It is important to suspect intestinal malrotation in older children that present with recurrent episodes of abdominal pain associated with symptoms of intestinal obstruction pain, irritability, vomiting, or failure to thrive.

For patients who are symptomatic as a result of malrotation, surgery is the treatment of choice. When it comes to asymptomatic malrotation, there is a lack of consensus. There are no prospective studies and only retrospective chart reviews and computer modeling.⁵ The questions that often arise are:

1. Are there asymptomatic patients that should be screened for malrotation?
2. If malrotation is found, what should the next step be? Should an elective Ladd’s procedure be performed or should observation be instituted ⁵? Surgery is a consideration in these asymptomatic patients because volvulus is a theorhetical risk.

Graziano et al. summarized the available literature and concluded that there was a lack of evidence to support screening asymptomatic patients for malrotation. Also, there was minimal evidence to screen those patients with heterotaxy syndrome (HS).⁶ Patients with HS have cardiac and visceral malpositionining. In these patients, volvulous most commonly occurs in the first year of life and most cases occur in the first month of life.^7,8 A recent literature review performed by Landisch, et al. found that 47% of patients with HS have intestinal rotation abnormalities on upper gastrointestinal series, but only 1.2% have an increased risk of developing volvulus.⁷ Pockett et al. found that 57% of patients with HS have serious complications and argued against prophylactic Ladd procedure.

What is true is that prospective data is needed and in the interim, we recommended that with each malrotation, the physician carefully weigh their experience and how it coincides with patient outcomes. From a pediatric gastroenterology perspective, we follow our field’s common adage-once a malrotation, always a malrotation. We therefore observe until clinical symptoms tell us otherwise.

Liver Disorders, Series #4

Primary Biliary Cholangitis

January 2016 • Volume XL, Issue 1

Gaurav Singhvi

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a chronic, cholestatic, inflammatory liver disease characterized by destruction of intrahepatic bile ducts resulting in progressive liver damage. The etiology of PBC is still not fully understood but likely involves both environmental and genetic factors. Here we provide a review of the etiology, pathogenesis, natural history, diagnosis and management of primary biliary cholangitis.

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A Case Report

An Unusual Presentation of Myopathy in Celiac Disease

January 2016 • Volume XL, Issue 1

John R. Stroehlein,Martin Poliak,Huamin Wang

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Although celiac disease in adults is more often manifest by non-gastrointestinal pathology or nutritional deficiency, indeterminate gastrointestinal symptoms combined with hepatopathy and myopathy can be an indication of celiac disease despite a normal anti TTG and serum IgA. This case illustrates a.) the importance of small bowel biopsy to render a diagnosis of celiac disease and b.) the potential for myopathy to occur without overt myositis, obvious nutritional deficiencies or metabolic bone disease. Celiac disease should be considered and pursued as a diagnostic possibility when the cause of weight loss and myopathy is indeterminate.

Although rare, the development of combined myopathy and hepatopathy from celiac disease is of clinical importance and requires consideration when gastrointestinal symptoms are associated a combination of markedly elevated creatine kinase and loss of muscle mass. This is illustrated by the following case which calls attention to the possibility of celiac disease as the basis for myopathy and hepatopathy.

A 66 year-old Caucasian female with a history of breast cancer developed acute onset of diarrhea beginning in February 2011. Her history included stress related irritable bowel symptoms, not necessarily with diarrhea, and reflux managed with a proton pump inhibitor. Recent upper and lower endoscopy were reported to be normal. She was empirically treated with ciprofloxacin and metronidazole by her primary physician. Her diarrhea improved but did not resolve and was followed by myalgia, fatigue, noticeable muscle loss without muscle tenderness and general weakness without electrolyte abnormalities. Subsequent treatment with a yogurt based probiotic, hyoscyamine and rifaximin were unsuccessful. Notable physical exam findings were limited to loss of muscle mass. She was referred for evaluation 6 months later; at that time, stool evaluation (C. difficile, ova and parasites and culture) was negative but lactoferrin was positive. Colonoscopy with biopsies performed elsewhere in October 2011 was negative for microscopic colitis. Her with consistently normal alkaline phosphatase and bilirubin. A normal gamma glutamyl transpeptidase (GGT) and negative viral serology prompted evaluation of the creatine kinase which proved to be 355 U/L and rose to 561 U/L as of December. Duodenal biopsies obtained during esophagogastroduodenoscopy (EGD) revealed chronic inflammatory change, villous atrophy and intraepithelial lymphocytosis, suggestive of celiac disease (Figure 1A & 1B). A gluten free diet was initiated and was followed by prompt normalization of all biochemical abnormalities with subsequent 35 pound weight gain and restoration of muscle mass. All of the patient’s symptoms resolved and have remained resolved, and the liver enzymes and creatine kinase have remained normal (Figure 2).

This index case exemplifies the possibility for myopathy to occur as a consequence of celiac disease. The possibility of myopathy was initially considered when the GGT was normal despite significant elevation of the ALT and AST. Additionally, duodenal biopsies are often necessary to establish the diagnosis of celiac disease in the absence of hypokalemia or other electrolyte abnormalities.¹ Prior case reports of celiacinduced myopathy have been reported in children.^2-3 Celiac disease associated myopathy may be more commonly encountered alongside other manifestations of gluten-sensitive enteropathy including metabolic bone disease^4-6 and polyneuropathy⁷ or, even more rare, myelopathy. There has been interest in the association of myotonic dystrophy and celiac disease although the response to gluten restriction is not predictable. Our case was not characterized by the aforementioned associations nor was there evidence of an inflammatory myopathy, which is often associated with higher levels of creatine kinase and elevation of the sedimentation rate. Although response to gluten restriction is not assured, the mere fact that there is no specific treatment for otherwise idiopathic inflammatory myopathy renders the association with celiac disease to be of more than passing interest.⁸

The association between celiac disease and neuromuscular disorders is not well defined; however, it is clear that celiac disease can manifest primarily if not exclusively with neuromuscular pathology. Myopathy is the third most common neuromuscular disorder associated with sprue and second only to ataxia and peripheral neuropathy.⁹ In addition to a clinical association between celiac disease and neuromuscular manifestation is the presence of IgA deposits against transglutaminase 2 observed in muscle in a patient with celiac disease.¹⁰ Interestingly, the antigen that endomysial antibodies recognize is tissue transglutaminase type 2. It is important to recognize the possibility that celiac disease can present with extra intestinal manifestations including unexplained myopathy.

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Frontiers In Endoscopy, Series # 24

Extension of a Prior Biliary or Pancreatic Sphincterotomy: Efficacy, Outcomes, and Adverse Events

January 2016 • Volume XL, Issue 1

Sheeva Parbhu,

Douglas G. Adler

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Endoscopic sphincterotomy (ES) is a complex procedure performed under direct endoscopic observation. ES is performed for a variety of both biliary and pancreatic disorders, including the treatment of biliary and pancreatic leaks, to facilitate the placement of biliary or pancreatic stents, as a precursor to cholangioscopy and/or pancreatoscopy, and to treat suspected sphincter of Oddi dysfunction. The need for repeat sphincterotomy can arise in clinical practice and interventionalists should be prepared to perform this when it is needed. In this article we discuss the efficacy, outcomes, and adverse events associated with these procedures.

Sheeva Parbhu, MD, Douglas G. Adler MD, FACG, AGAF, FASGE, University of Utah School of Medicine, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Huntsman Cancer Center, Salt Lake City, UT

INTRODUCTION

Endoscopic sphincterotomy (ES) is one of the most fundamental maneuvers performed in ERCP, with over 150,000 biliary sphincterotomies performed annually in the United States.¹ ES is a complex procedure performed under direct endoscopic observation. Facilitating the removal of common bile duct stones is the most common indication, but ES is performed for a variety of both biliary and pancreatic disorders, including the treatment of biliary and pancreatic leaks, to facilitate the placement of biliary or pancreatic stents, as a precursor to cholangioscopy and/or pancreatoscopy, and to treat suspected sphincter of Oddi dysfunction, among others (see Table 1).^2,3

ES, also known as sphincterotomy or papillotomy, involves retrograde cannulation of the bile or pancreatic duct via the ampulla of Vater. In the vast majority of sphincterotomies, ES is performed after deep access to the desired duct has been achieved and a guidewire is in place in the duct. The biliary or pancreatic sphincter is then incised by a sphincterotome via electrocautery delivered through the cutting wire incorporated into the sphincterotome itself.

Less commonly, a needle knife instead of a sphincterotome is used in order to perform ES, usually in cases where standard techniques to achieve ductal access have failed. Other variations of the technique include a precut sphincterotomy (cutting with a sphincterotome without deep access already established) as well as transpancreatic sphincterotomy also known as a trans- septal sphincterotomy. In rare cases, an interventional radiologist can assist in a combined percutaneous- endoscopic procedure by passing a guide-wire in an antegrade manner through the bile duct and into the duodenum to allow the endoscopist to achieve ductal access and perform sphincterotomy.1

Complications of Initial Biliary Sphincterotomy

Complications related to performing ES vary greatly, from approximately 6-22% in multiple studies.^4,5,6 Freeman et al. conducted the largest prospective study, consisting of 2347 patients analyzing complications of ES. They identified difficult cannulation of the duodenal sphincter, use of precut sphincterotomy, suspected sphincter of Oddi dysfunction and presence of cirrhosis as significant factors associated with an increased odds ratio of procedure-related complications. The authors concluded that complications were related to the technical skill of the endoscopist, indicating that these procedures may be safest in centers in that perform ES on a regular basis.¹ Complications are likely less common with high volume providers.

A different study that investigated the risk of post- ERCP pancreatitis (PEP) in the setting of ES identified a relative increase in risk in younger patients and patients who received an increased number of contrast injections into the pancreatic duct.7 More recent retrospective data has identified the co-morbid conditions of chronic kidney disease (possibly with associated platelet dysfunction from uremia), hypertension and ischemic heart disease as risk factors in post-procedural bleeding after ES.⁸

The type of current used for electrocautery has also been described as a risk factor for complications related to ES. Pure current provides better tissue cutting quality, whereas mixed current combines pure current with low-voltage coagulating current in alternating short bursts, achieving cutting and coagulation simultaneously.^9,10 Multiple prospective randomized trials have been unable to identify a clearly superior method of electrocautery in relation to specific side- effects.^11,12 A meta-analysis of 4 trials and over 800 patients identified no significant difference in rate of pancreatitis, however pure current was noted to be associated with more episodes of bleeding compared to the mixed current technique.¹³

Specific complications related to performing ES are most commonly classified as early (occurring within 30 days of the procedure) or late (occurring > 30 days after the procedure). The overall rate of early complications has been quoted around 7-10% in various studies, and most commonly includes bleeding (both immediate and delayed hemorrhage), pancreatitis, and rarely, duodenal perforation.^1,13,14 A major late complication of ES is papillary restenosis, which can occur months to years after initial ES. This complication is rare but has been noted in 1-4% of patients, and can be successfully treated with repeat ERCP and ES.^2,3,15 Ascending cholangitis is another late ES complication managed by repeat ERCP.³ Recurrent stones can also be seen in these patients, but it is unclear if this represents a procedure-related complication or the natural course of stone-related disease.¹⁵

Throughout the literature there is mention of the long-term risk of patients with ES developing cholangiocarcinoma, presumably through chronic inflammation resulting in malignant transformation or through sample error as those undergoing ERCP are more likely to have underlying biliary disease in the first place. However, several studies with long-term follow up (greater than 10-15 years) have been unable to confirm this suspected link. ^5,15,16,17

Repeat Biliary Sphincterotomy
When and Why?

A problem for any endoscopist who performs ERCP is the occasional need to extend a previous sphincterotomy. This can occur at any time, from days to years after the initial procedure.

The need for a repeat procedure can be divided into the “early” and the “late” time period, although what exactly is meant by these terms has been variably defined in the literature. A retrospective review of 248 patients defined an early post-procedure period of 1-3 days, and differentiated it from the period 4-10 days after the original sphincterotomy.¹⁸ Although seemingly arbitrary and not based on rigorous evidence, this division was made because of the anecdotal experience that re-intervention within 3 days may be met with increased technical difficulty. This increase in difficulty is thought to be related to persistent edema from recent trauma, as well as the potential presence of an adherent clot, which can obscure vision and carries with it a higher risk of bleeding.¹⁹ Alternatively, Mavrogiannis et al conducted the largest prospective study to date and used 0-8 days as the early re-intervention group, whereas the late reintervention group had a repeat procedure between 9 days to 7 years from the initial ES.²⁰ This was done because several early studies had identified a high risk of bleeding in patients within 8 days of ES, attributed to increased papillary vascularity during that time.²¹

Regardless of the specific timing, early extension of prior ES can be performed for several different indications. The most common reason to extend a biliary sphincterotomy is to facilitate the removal of biliary stones that could not be removed on a prior ERCP. (Figures 1 and 2) Other patients need their sphincterotomy extended and completed after it was interrupted during the initial procedure due to various complications (bleeding, severe edema, periampullary diverticulum, and cardiopulmonary complications related to sedation). Another reason for extension of ES is to complete a sphincterotomy after the precut technique has been used.¹⁹

Although the exact definition of a “late” extension of previous sphincterotomy may be debated, it is commonly needed in the setting of papillary stenosis which can develop after a prior biliary ES, although true papillary stenosis is a rare development. Sphincterotomy extension can also be necessary to remove common bile duct stones that recur.²⁰

Papillary stenosis may cause jaundice or other associated conditions like stone formation and/or cholangitis. The development of stenosis at the site of prior sphincterotomy is thought to be due to inadequate incision of the sphincter muscle or excessive scar tissue formation. It is frequently seen in patients who have had extraction of multiple or large stones compared to patients who have sphincter of Oddi dysfunction or pass single, small stones.²² It could also be related to fibrotic reaction at the site of incision, as previous studies have shown that mean length of incision does decrease over time, indicating an active area of tissue growth and re- modeling.²³ Late extension is sometimes not possible, as Bourke et al first described the phenomenon of a papillary orifice that is seemingly buried in the duodenal wall. In this situation, the papillary stenosis extends along the bile duct beyond the biliary orifice, and the lesion is not amenable to further extension.²⁴ This situation is, fortunately, extremely uncommon.

Outcomes, Safety and Adverse Events

The largest prospective study of extending a biliary ES followed 250 patients who underwent sphincterotomy as primary treatment for choledocholithiasis. Of those, 81 (32%) underwent extension of their initial ES. 66 of these patients underwent a “late” extension (9 days to 7 years after initial procedure), while the remaining 15 had an early extension within 8 days of the first ES. 80 out of the 81 patients had successful clearance of stones from the bile duct after repeat ES, with mechanical lithotripsy utilized in one case. The authors concluded that extension of a previous sphincterotomy is an efficient treatment for recurrent biliary stones. It should be noted that the cohort represented a homogenous group of patients with choledocholithiasis, and patients with other indications for repeat ES were excluded.20

This study concluded that repeat ES was a safe procedure, with an overall complication rate which was no different when compared to the initial sphincterotomy group (2.5% vs 8.4%, p > 0.05). Other common complications, including bleeding, cholangitis and perforation were found to be the same in both groups, with no deaths reported in either group. The repeat ES group did, however, have statistically significant fewer episodes of pancreatitis (0% vs 4.8%, p < 0.05). This suggests that extension of previous sphincterotomies may have less risk of pancreatic injury than initial ES, possibly explained by cutting on the upper edge of the previous cut, thus avoiding the pancreatic orifice. There was a trend (although not statistically significant) towards a higher risk of bleeding in early repeat ES vs late repeat ES. Both cases of bleeding in this cohort occurred when repeat ES was performed within 3 days of initial ES.20

A similar study aimed to examine whether repeat ERCP was safe and feasible in treating recurrent choledocholithiasis. Resembling the design of Mavrogiannis et al, the study excluded patients with concomitant hepatolithiasis, choledochal cysts or bile duct strictures. Of 84 patients who underwent repeat ERCP for post-ES recurrent choledocholithiasis, 69 patients received a repeat sphincterotomy. Biliary duct clearance was achieved in 100% of these patients. Early adverse events were noted in 2 (2%) patients. This low complication rate consisted of cases of mild pancreatitis and mild hemorrhage.²⁵

In addition to confirming that repeat ES is indeed a safe procedure in the short-term, this study was unique in that it also included long-term follow up (mean 11.7 years) after repeat ERCP. Choledochal complications, consisting of recurrent choledocholithiasis and cholangitis were noted in 30 patients during this follow- up period. While this rate of 36% is higher than the complication rates reported after initial ES (6-22%), the authors explained this by identifying independent risk factors not related to the procedure. Multivariate analysis found that early recurrent choledocholithiasis (within 5 years), a dilated bile duct ( >15mm) and periampullary diverticulum were independent risk factors predictive of these recurrent stone disease and cholangitis.²⁵ While this study confirmed that repeat ERCP and ES are safe and effective means of managing recurrent biliary disease, the simple fact that patients require a repeat procedure seems to put them at increased risk for further complications and future procedures.

A more recent study investigating the safety and efficacy of repeat ES was described by Hisai et al.²⁶ They describe a series of 76 patients who underwent repeat ES, 25 of whom had a repeat procedure within 8 days of the initial procedure (“early” extension), and 51 who received a “late” extension ( > 9 days after initial procedure). This delineation of early and late was the same as described by Mavrogiannis et al.²⁰ While recurrent choledocholithiasis was the most common indication for repeat ES (67/81 patients, 83%), this study included patients requiring ES for other indications, including biliary strictures and papillary stenosis. Repeat ES was technically successful in all cases, with an overall complication rate of 5.4%. Complications consisted of bleeding (2 patients), mild pancreatitis (2 patients) and cholangitis (1 patient). The overall complication rate, including pancreatitis, was no different between the two groups, and there were no procedure-related deaths. The authors concluded that repeat ES is safe, effective and was not associated with an increased risk of bleeding as they had hypothesized.²⁶

Pancreatic Sphincterotomy
Indications for and Complications of Initial Pancreatic Sphincterotomy

The sphincter of Oddi can be anatomically divided into the bile duct (biliary) sphincter, the pancreatic duct sphincter, and the ampullary sphincter, encompassing the distal most portion of the ampulla. In biliary endoscopic sphincterotomy, the pancreatic sphincter is left intact.²⁷ Pancreatic sphincterotomy was first described in 1976 and can be performed in conditions such as pancreas divisum, chronic pancreatitis, to perform pancreatoscopy, to facilitate the evaluation of pancreatic malignancy, to enable the remoal of pancreatic stones (pancreaticoliths), and to treat suspected pancreatic sphincter of Oddi dysfunction.^28,29

Pancreas divisum is a relatively common congenital abnormality of the pancreatic ductal system, occurring in about 7% of the population in the United States.²⁹ While typically asymptomatic, it can be associated with recurrent acute or chronic pancreatitis, as well as chronic abdominal pain. Most studies evaluating the success of pancreatic ES in these patients consist of retrospective case series measuring pain burden, and the success rates vary widely from 32%-86%.^30,31 Of note, pancreatic sphincterotomy in patients with pancreas divisum is performed on the minor papilla, which is distinct from pancreatic ES for other indications.

Pancreatic ES of the major papilla is useful in chronic pancreatitis, as it can improve pancreatic drainage via facilitating the removal of stones and endoscopic of strictures in the pancreatic duct.²⁹ While technical success rates of the procedure are high ( > 85%), the number of patients who clinically improve after the procedure is lower, around 50% in several studies.^32,33

A more controversial indication, the treatment of sphincter of Oddi dysfunction, is another indication for pancreatic ES, biliary ES, or both. In patients with abnormal sphincter manometry, clinical improvement after ES has been quoted as 85%-95% in earlier studies.^34,35 A recent, widely publicized, randomized sham controlled, multicenter trial studied over 200 patients with sphincter of Oddi type III dysfunction. Their results were far less enthusiastic and demonstrated that in these patients, pancreatic and/or biliary ES does not improve outcomes, and sphincter manometric pressure is not predictive of pain relief, lessening the enthusiasm for this procedure in some circles.³⁶

The major early complications associated with pancreatic ES are bleeding, cholangitis and pancreatitis.²⁹ As would be expected, the overall rate of pancreatitis in patients undergoing pancreatic ES is higher than the risk after ERCP without pancreatic ES. Overall, the rate of pancreatitis following pancreatic ES is around 10-12%, while the rate of post-ERCP pancreatitis has been quoted at approximately 3% in expert hands, and is likely higher in the hands of low volume providers.^37,38,39 The incidence of pancreatitis after pancreatic ES can be affected by other factors, including pancreatic duct stent placement, difficulty of cannulation of the pancreatic duct, and whether the pancreatic sphincterotomy was performed on the major or minor papilla.⁴⁰ Stent-related complications, including parenchymal changes, infection, perforation, occlusion and stone formation can be seen in follow- up if stents are left in the pancreatic duct too long, but are not related to the sphincterotomy itself.⁴¹ Late complications such as papillary stenosis and proximal ductal strictures are exceedingly rare, and can similarly be treated with repeat pancreatic ES.

Repeat Pancreatic Sphincterotomy

Pancreatic ES is performed far less frequently than biliary ES. This is due to less commonly encountered indications for the procedure, as well as operator concern regarding the technical difficulties and the perceived increased occurrence of complications.⁴⁰ As a result, the literature is sparse regarding incidence, safety and specific complications in regards to repeat endoscopic pancreatic sphincterotomy. Still, repeat pancreatic sphincterotomy is a valid procedure that is sometimes clinically indicated, most commonly to allow removal of pancreatic duct stones. (Figure 3)

Jakobs et al. retrospectively identified 171 patients who underwent pancreatic ES for therapy of chronic pancreatitis over the span of 11 years.⁴² The procedure was technically successful on the first attempt in 147 patients (86%). In the remaining 24 patients, repeat pancreatic ES (maximum of 3 attempts) was successful in 20 (83%) patients. During the long-term follow- up period, a repeat pancreatic sphincterotomy was necessary in 17/167 patients (10%), and was successful in all patients. Indications for repeat sphincterotomy were an inadequate pancreatic duct orifice for removal of pancreatic duct stones (13 patients), retrieval of a pancreatic duct stent (2 patients) or transpapillary insertion of a larger pancreatic stent (2 patients).⁴²

A similar retrospective study by Joo et al. identified 46 patients who underwent pancreatic ES.⁴⁰ While a majority (26/46 or 57%) of patients received pancreatic ES for the indication of chronic pancreatitis, 10/46 (22%) were undergoing evaluation for possible malignancy, for cases of pancreatic divisum (4/46) (9%), and for treatment of pancreatic pseudocyst (3/46) (7%). The procedure was successful in 96% (44/46) of patient, and the authors only reported one late complication of re-stenosis of the pancreatic duct, which developed after 38 months. The need for repeat sphincterotomy in only 2% (1/46) of patients is explained by the authors as being due to the heterogenous characteristics of the study cohort, as well as the relatively large amount of patients (12/46 or 26%) that were lost to follow-up.⁴⁰

A recent large prospective study examining the effectiveness of ES in patients with chronic pancreatitis prospectively followed a 41 patient sub-set who received a pancreatic ES in addition to ductal dilation and/or stent placement. The mean follow-up period was 4.8 years, and there were no reported long-term complications that required repeat pancreatic ES. While the study’s primary aim was to compare outcomes in patients who underwent different modalities of treatment, it contributes to the conclusion that pancreatic ES is a safe and effective procedure without significant long- term complications.³²

Initial and Repeat Sphincterotomy of the Minor Papilla

In contrast, pancreatic ES performed on the minor papilla in patients with pancreatic divisum (PD) is considered a separate clinical and technical entity. For patients with symptomatic PD, it is postulated that obstruction at the site of the accessory pancreatic duct, or minor papilla, is an important predisposing factor for symptomatic disease. By receiving therapy to relieve the obstruction and improve pancreatic drainage, it is thought that symptoms such as pain and recurrent acute pancreatitis may be relieved.43 Successful endoscopic therapy via pancreatic ES, which consists of resolved pain and decreased instances of pancreatitis, has been reported to occur in up to 60-80% of patients in some studies. This varies based on patient characteristics and this number is likely elevated due to some degree of publication bias.^44,45

Pancreatic ES at the minor papilla incurs similar risks of acute complications, including pancreatitis, bleeding and perforation.⁴⁶ The rate of pancreatitis, however, has been noted to be higher in patients undergoing pancreatic ES of the minor papilla, with some studies citing an incidence in over 30% of patients.⁴⁷ More recent studies have shown that if the intervention is performed by an experienced endoscopist at a large referral volume center, the rate of pancreatitis may decrease significantly, to below 10%.^44,48 The rate of re-stenosis in these patients is a significant long-term complication, ranging from 16-20%. This results in the need for re-intervention, often with repeat pancreatic ES.^45,49

In a large retrospective review of 184 patients, Atwood et al compared differences in outcomes between needle-knife sphincterotomy and standard pull-type sphincterotomy of the minor papilla.⁴⁴ Complication rates and outcomes were the same in both groups, with the authors indicating that endoscopist preference and comfort plays a large role in which technique is safest. Re-stenosis rates were around 20%, and were not different between the two groups. In this study, median follow-up over the span of 5-6 years identified 28 patients (21%) who required repeat pancreatic ES. A majority of these patients received their repeat procedure within a year of the index procedure, and the need for a repeat ES did not seem to be a risk factor for further complications.⁴⁴

Another retrospective study that included 113 patients attempted to evaluate long-term clinical outcomes in patients who underwent ES of the minor papilla. Over a median follow-up range of 47 months, the overall success rate was 62%. While primary success (no need for repeat procedure) was noted in 49/113 (43%) patients, another 47/133 (42%) patients required at least one more ERCP. While the authors did not publish data regarding how many of those patients needed a repeat or extension of minor papilla ES, they did mention restenosis as a complication seen in follow- up that was safely treated via a repeat ES.⁵⁰

Maple et al. described a retrospective study of 64 patients undergoing minor papilla ES to compare a wire- assisted technique compared to the aforementioned needle-knife or pull-type sphincterotomies. While no significant difference existed between the techniques, the published data included a sub-set of patients who required re-intervention. The authors reported 11/64 (17%) patients who required a repeat intervention on the minor papilla. No complications were reported in these procedures, and all were technically successful.⁵¹

CONCLUSION

Endoscopic sphincterotomy remains a fundamental maneuver during ERCP, and the need for repeat sphincterotomy can arise in clinical practice and interventionalists should be prepared to perform this when it is needed. Complications of extension of an ES tend to be linked to characteristics of the patients, the indication for the procedure, and the technical skill and experience of the endoscopist. Patients who undergo biliary ES tend to be at risk to undergo further endoscopic therapy, likely related to their underlying disease process and not the sphincterotomy itself. Distinct “early” and “late” re-interventions are well described in the setting of biliary ES, and studies have shown that these repeat procedures are safe and effective. While the field still lacks multiple prospective clinical trials to confirm this, repeat biliary ES is a necessary procedure that can be performed without excessive risk of adverse events.

Although sparse and lacking randomized prospective data, the summation of the literature regarding extension of a prior pancreatic ES supports the fact that it can also achieve good outcomes when patients are properly selected. Some pancreatic ES patients do require repeat procedures, and while re- intervention is also relatively safe, it is a fact that should be taken into account when deciding on initial therapy.

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INTRODUCTION

CASE

DISCUSSION

INTRODUCTION

Effects of Liver Diseases on the Heart

Effects of Liver Diseases on the Respiratory System

Effects of Liver Diseases on the Nervous System

Hepatic Encephalopathy Associated Central Nervous System Damage

Non-Hepatic Encepahalopathy Related Central Nervous System Damage

Effects of Liver Diseases on the Skin

Pruritus

Prurigo Nodularis

Lichen Planus

Vitiligo

Dupuyntren’s Contracture

Cutaneous Vascular Signs

Effects of Liver Diseases on the Renal System

Hepatorenal Syndrome(HRS)

Hepatitis Associated Renal Disease

Effects of Liver Diseases on the Blood Platelet Abnormalities

Coagulopathy

Erythrocyte Abnormalities

Leuckocyte Abnormalities

Endocrine and the Liver

Thyroid Dysfunction in Liver Disease

Diabetes Mellitus, Lipids and the Liver

Adrenal Diseases and the Liver

Liver Diseases and Nutrition

Effects of Liver Diseases on Other Organ Systems

Ophthalmic System

Drug Induced Liver Diseases

CONCLUSION

INTRODUCTION

Case Presentation

Discussion

Take Home Message

INTRODUCTION

Case Report

Discussion

INTRODUCTION

Incidence of Proximally Migrated Stents

Complications of Proximally Migrated Biliary Stents

Complications of Proximally Migrated Pancreatic Stents

Retrieval Techniques

Plastic Biliary Stents

Metal Biliary Stents

Pancreatic Stents

Endoscopic Failure-Indications for Surgery

CONCLUSION

INTRODUCTION

Epidemiology

Clinical Presentation

Diagnosis

Treatment

Discussion

CLINICAL PEARLS

INTRODUCTION

Complications of Initial Biliary Sphincterotomy

Repeat Biliary Sphincterotomy When and Why?

Outcomes, Safety and Adverse Events

Pancreatic Sphincterotomy Indications for and Complications of Initial Pancreatic Sphincterotomy

Repeat Pancreatic Sphincterotomy

Initial and Repeat Sphincterotomy of the Minor Papilla

CONCLUSION

Effects of Liver Diseases on the Blood
Platelet Abnormalities

Repeat Biliary Sphincterotomy
When and Why?

Pancreatic Sphincterotomy
Indications for and Complications of Initial Pancreatic Sphincterotomy