Hepatobiliary Quiz (Answers)—14 (2015)

• 1.Correct answers: B, C and E

Ammonia is primarily metabolized in the liver by the urea cycle under normal conditions. The leftover ammonia is detoxified by the enzyme glutamate synthetase (GS), which converts the ammonia into glutamine. GS is found in the hepatocytes surrounding the hepatic veins, muscle cells and astrocytes.^1,2 Within the CNS, GS is located exclusively within the astrocytes. Thus, these cells bear the brunt of the toxic effects of ammonia, in turn leaving the neurons completely unaffected by the exposure.^3–5 In patients with cirrhosis, astrocytes exhibit features of Alzheimer Type II astrocytosis, which include nuclear swelling, enlargement of cytoplasm and margination of chromatin. These changes may also be seen in patients with urea cycle defects and experimental models of hyperammonemia.^2,6,7

Within the astrocytes, ammonia combines with glutamate to form glutamine. This leads to reduced levels of glutamate in the cell, a deficiency that is partly compensated by conversion of α-ketoglutarate to glutamate.⁸ The removal of α-ketoglutarate and the fact that ammonia is an inhibitor of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase leads to high levels of lactate and pyruvate in the brain.⁹

The pathogenesis of hepatic encephalopathy (HE) was previously thought to be solely a function of hyperammonemia. However, it is now known that inflammation, oxidative and nitrosative stress all play a role as well. Alterations in the gut mictobiota, in tandem with the underlying immune dysfunction and leaky mucosal barrier, play an important role in the pathogenesis of HE.^10,11

• 2.Correct answers: D and E

Intracranial Hypertension (ICH) was previously believed to be present in upto 80% patients with Acute Liver Failure (ALF).¹² However, recent data suggests that only about 20–25% cases of ALF have ICH. Among the patients who develop ICH, mortality rates are found to be much lesser. This may be due to earlier recognition of the severity of the disease, leading to better medical care and use of salvage emergency transplant.^2,13,14

The brain lacks an effective urea cycle, thus leaving the removal of ammonia exclusively to the glutamate synthetase in the astrocytes. In ALF, the brain edema is primarily cytotoxic in nature, resulting from astrocyte swelling. The blood–brain barrier permeability is not grossly altered.^15–17

Glutamine levels in the brain are significantly increased in patients with ALF. Previously, these levels were not found to correlate with the severity of encephalopathy or presence of cerebral edema.^15,18,19 However, a recent study has shown a progressive increase in glutamine and glutamate peak on magnetic resonance spectroscopy with the increase in severity of HE.²⁰

• 3.Correct answers: B, C and E

Overt HE (OHE) occurs in approximately 30%–50% of patients with cirrhosis, while MHE is seen in 30–84% of patients with cirrhosis who do not have OHE. Among those with MHE, over 50% develop OHE over a follow up of 3 yrs^21–24 Patients who develop MHE are older, more often have alcohol as etiology of cirrhosis, have history of overt HE in the past, have more severe liver disease, and more often have esophageal and gastric varices. Once patients with recent alcohol intake were excluded, the prevalence does not vary with the etiology of cirrhosis.^25–28

• 4.Correct answers: B, D and E

Cirrhotic patients with HE show increased cerebral water content. Magnetization transfer ratio decreases according to the degree of HE, which signifies an increase in brain water content. Quantitative MR experiments show a rise in brain water as HE progresses.^29,30 Also, a decrease in apparent diffusion coefficient (ADC) after the resolution of HE suggests an increase of extracellular water during an episode of HE. Conversely, HE due to ALF shows evidence of increased brain water content.³¹⁻³³ MRS studies showed a progressive increase in glutamine and glutamate peak according to the severity of HE. Moreover, on resolution of HE, a decrease in glutamine and glutamate peak is observed.^20,34 However, changes in choline derivates or N- acetyl aspartate are not seen except in advanced HE.^20,35,36 Voxel Based Morphometry facilitates volumetric studies of brain. This technique shows that cirrhotic patients have a decrease in gray matter volume and an increase in white matter volume as compared to healthy controls. This difference is further aggravated with the progression of HE.^37,38

• 5.Correct answers: C and E

Rifaximin is a broad spectrum antibiotic similar to rifampin structurally. However, it contains a benzimidazole ring, by virtue of which its systemic absorption is reduced to <0.4%.³⁹ It binds to bacterial DNA-dependent RNA polymerase and inhibits bacterial RNA and protein synthesis. It is mainly excreted via feces. Rifaximin modulates the intestinal flora such that there is reduced intestinal ammonia and toxin formation. There is a reduction in Veillonellaceae (gram negative cocci) and an increase in Eubacteriaceae (gram positive cocci).^40,41 Rifaximin is effective and well tolerated, with minimal systemic absorption. A meta-analysis comparing rifaximin with lactulose found that patients taking rifaximin fared better than those on lactulose.⁴² Two recent meta-analyses suggest that rifaximin may not be superior to non-absorbable disaccharides. However, it is clear that it is at least equally effective as lactulose.^43,44

Rifaximin is a safe antibiotic and has not been found to be associated with Clostridium difficile associated diarrhea.⁴⁵

• 6.Correct answers: A, B and C

40–50% of patients with Wilson's Disease (WD) present with neurological symptoms.^46,47 The presentation is usually between 20- and 30-years. Tremor is the most frequent neurological symptom, seen in up to 80%, followed by a Parkinsonian-like syndrome (40%).⁴⁸ In up to 25% cases, psychiatric symptoms may be the initial presentation.^49–51 Overall, psychiatric manifestations may be seen in 65% cases most common symptom being personality disorders (seen in 46–71% cases). Mood disorders are the second most common group of psychiatric abnormalities. Sometimes symptoms of WD and HE may overlap, esp. in advanced disease. In such cases, electroencephalogram can help in differentiating the two. The typical EEG waves of HE are not seen in neurological presentation of WD.

• 7.Correct answers: B, C, D and E

HE and WD may show similar clinical neuropsychiatric signs and symptoms in the milder stages of the disease. There is metal deposition in the basal ganglia in both disorders (copper in WD, manganese in HE) lead to further neuronal degeneration with additional cortical and subcortical abnormalities. There is disruption of dopaminergic transmission. MRI in HE shows hyperintensive changes in T-1 weighted images in both globi pallidi due to manganese accumulation.^48,52 In WD hyperintensive changes in T-2 weighted MRI in basal ganglia, thalami and brainstem are seen due to copper deposition. These can also be seen on a computed tomography (CT) scan.⁵³ MRS can be used to analyze the concentrations of various metabolites. In WD there is a decrease in N-acetyl-aspartate (NAA), which is a characteristic marker of neuron damage and depletion. This is seen in HE only in advanced stages. However, at very early stages of both disorders the picture could quite similar.⁵³ MRS changes observed in HE are reversible after liver transplantation or pharmacological treatment.^35,54,55

• 8.Correct answer: A

ICP measurement is indicated in patients of ALF who have grade 3 or 4 encephalopathy. Epidural transducers are used most commonly and carry the lowest complication rate (3.8%). Subdural bolts and parenchymal monitors carry complication rates (mainly bleeding) of 20% and 22% respectively. The average ICP ranges from 0 to 10 mmHg. The goal of management is to maintain an ICP <20 mmHg and cerebral perfusion pressure (CPP) above 50 mmHg. ICP >40 mmHg for >2 h or CPP <50 mmHg preclude liver transplantation in patients with ALF.^56,57

A jugular bulb catheter may be used to sample the jugular venous blood. Saturation of <55% represents an ischemic brain, and indicate need to improve oxygenation of the patient.⁵⁸ Mannitol is one of the most commonly used osmotic agent in the management of ALF. It lowers the ICP by reducing the brain water and changing the rheological characteristics of blood. Its ICP lowering action is optimal in cases of mild to moderate ICH, and is less effective when the ICP is greater than 60 mmHg.^56,59 Moderate hypothermia (32°C–35 °C) leads to a reduction in intracranial pressure in patients with ALF. The cerebral metabolism, ammonia uptake by the brain, and glutamine synthesis are also reduced. However it does not improve survival. It is mainly used as a bridge to transplantation^60–62

• 9.Correct answers: A and E

Coexistence of malarial hepatopathy and cerebral malaria can frequently mimic ALF. Most of the cases have Plasmodium falciparum or combined P. falciparum and Plasmodium vivax infection. P. vivax alone rarely presents with this syndrome.^63–65 Jaundice may be seen in 5.3% cases of falciparum malaria, and is multifactorial in origin.⁶⁶ Actual inflammation of liver parenchyma is almost never seen, unless there is a coexisting ongoing acute or chronic viral hepatitis. The liver function tests show a raised bilirubin, which is mostly conjugated, and a rise in alanine transaminases over 3 times normal.^67–69 Prothrombin time is normal, even if enzymes are markedly elevated, unless there is coexisting disseminated intravascular coagulation.^70,71

• 10.Correct answers: A, D and E

Opportunist pathogens like cryptosporidium, isospora, cyclospora, cytomegalovirus, candida and mycobacterium avium–intracellulare complex can involve the biliary tree in patients with HIV with severe immunosuppression (CD4<200/mm³), leading to HIV cholangiopathy. These patients typically present with right upper quadrant pain, fever and elevated alkaline phosphatase. Jaundice may be seen, however it is uncommon in these patients. Most of the culprit agents infect the small bowel as well, and diarrhea is commonly associated. As many of these patients have severe immunodeficiency, altered sensorium is frequently seen, thereby mimicking features of liver failure.^72,73

Conflicts of interest

All authors have none to declare.