Hepatobiliary Quiz–12 (2014)

1. Correct answers: 1 and 4

Idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH) has been described by various terminologies such as idiopathic portal hypertension, non-cirrhotic portal fibrosis (NCPF), nodular regenerative hyperplasia (NRH), incomplete septal cirrhosis, partial nodular transformation of the liver, benign intrahepatic portal hypertension and hepatoportal sclerosis. Although, these diseases differ in some details in their description and defining criteria, they are believed to represent variations in appearance of a single pathological entity.¹ The basic pathology of NCIPH is narrowing or occlusion of 3rd/4th order portal vein radicles. Small portal vein radicles are obliterated or thrombosed with portal vein sclerosis and/or portal angiomatosis, peri-sinusoidal fibrosis and sinusoidal dilatation suggestive of obliterative portal venopathy (OPV).^2,3 In advanced stages thrombosis of the medium and large portal vein branches may be seen. The various morphological patterns of NRH, NCPF, incomplete septal fibrosis etc. may be histological spectrums of different stages of a single clinical entity cumulating in NCIPH.^4,5

While NCIPH is more common in developing countries it has been reported from all parts of the world. It is reported to be associated with low socio-economic groups. The disease is relatively rare in the West and even in developing countries there is a decline in its incidence in parallel with improving in living standards and hygienic conditions.⁶

2. Correct answers: 1, 4 and 5

The association of NCIPH with low socio-economic status, confinement of pathology to portal venous system and association with inflammatory diseases of the bowel suggest the role of intestinal derived pro-inflammatory factors in the pathogenesis of NCIPH.¹ Incidence of celiac disease in NCIPH is 16–20%, which is higher than the general population.^7,8 Pro-inflammatory stimuli from damaged gut cause expression of ultra-large von-Willebrand Factor (vWF) in portal venous endothelium. Normally the ADAMTS 13 cleave the long strands of vWF preventing platelet aggregation. With deficiency or absence of ADAMTS 13, ultra large vWF strings remain anchored to the endothelium and activate intraplatelet signaling by interacting with platelet glycoprotein 1ba resulting in platelet thrombi.⁹ Severe deficiency of ADAMTS 13 has been documented in NCIPH patients in the absence of confounding effect of liver disease.^10,11 Other conditions associated with NCIPH include common variable immunodeficiency, human immunodeficiency virus infection, inflammatory bowel disease, arsenic toxicity and treatment with oxaliplatin and azathioprine.

3. Correct answers: 1, 3 and 4

Mesenteric venous thrombosis can be acute or chronic. Acute MVT accounts for 6%–9% of all the cases of acute mesenteric ischemia, the rest usually being due to arterial thrombosis.¹² Acute MVT presents with pain abdomen in 90–100% cases which is usually out of proportion to physical findings.¹³ There is associated nausea and vomiting with hematochezia or melena seen in only 15% cases.¹⁴ Plain X-rays are insensitive for the diagnosis of mesenteric ischemia and the findings of thumbprinting, air in the intestines (Pneumatosis Intestinalis), air in the portal vein and free peritoneal air are late findings. Similarly, lactic acidosis is a late marker of bowel infarction and mortality is already 75% by this time. Diagnosis can be made reliably and early by contrast enhanced computed tomography.¹⁵

4. Correct answers: 3 and 5

Thrombosis of the large distal portion of the mesenteric vein is usually due to local diseases like malignancy, pancreatitis and infection and may be associated with portal vein thrombosis. Isolated MVT thrombosis involving the vena rectae is usually due to systemic prothrombotic states. Idiopathic MVT accounts for 21–49% of cases of MVT, with the proportion of idiopathic cases decreasing with detailed evaluation.¹⁴ Malignancies including myeloproliferative neoplasms are the most common prothrombotic states associated with MVT.¹² Oral contraceptive use accounts for 9–18% of cases in young women.^16,17 Other common prothrombotic states causing MVT include antithrombin III, protein S and protein C deficiencies, methylene tetrahydrofolate reductase mutations, factor V Leiden mutation and prothrombin transition G20210A. Patients may have more than one prothrombotic factor present with one study finding combined mutations 33% patients.¹⁵

5. Correct answers: 1 and 5

Many small human trials have evaluated the role of HBsAg based vaccination for the treatment of chronic hepatitis B virus (HBV), with only limited efficacy. This is because HBsAg vaccines do not develop immune response against covalently closed circular DNA (cccDNA) or HBcAg.¹⁸ Patients who have spontaneously been able to control HBV infection and limit liver damage have higher levels of HBcAg-specific cytotoxic T lymphocytes (CTLs) in the liver compared to patients who are unable to do so. While HBsAg-specific humoral immunity blocks HBV DNA and HBV-related antigens in the peripheral blood, cellular immunity against HBcAg control cccDNA in the liver and limit liver damage.^19,20 Trials of HBcAg based vaccine in a mouse model of HBV has shown lasting HBsAg negativity, development of anti-HBs and HBsAg and HBcAg-specific T lymphocytes in lymphoid tissue, and HBsAg and HBcAg-specific CTL in the liver.^21,22 One phase I/II trial in humans showed that combined HBsAg/HBcAg-based immunization was safe and resulted in sustained HBV DNA negativity in 50% of patients and persistent normalization of liver functions in all the patients in the study.²³ A phase III clinical trial is currently underway assessing the response of this vaccine in comparison to pegylated IFN therapy for 48 weeks [ClinicalTrials.gov: NCT01374308].

6. Correct answers: 2 and 4

According to data from 21 population based and 7 hospital based cancer registries, the age adjusted incidence rate of liver cancer in India is 0.7–7.5 for men and 0.2–2.2 per 100,000 persons per year for women.²⁴ There is a male preponderance with a male: female ratio of 4:1.²⁵ There is a significant increase in HCC incidence in Mumbai, Chennai and Bangalore registries over the past 2 decades.²⁶ Cirrhosis of any etiology is the single largest risk factor for development of HCC, with 70–90% of HCC developing in cirrhotic livers globally,²⁷ with similar figures of 70–97% reported from India.^28,29 HBV infection is the most common etiology of liver disease in patients with HCC in India, accounting for 71% and 64% of cases of HCC with and without cirrhosis.³⁰ Treatment of HBV and hepatitis C infection substantially reduces the risk of HCC. Even in patients who have cirrhosis or advanced fibrosis, lamivudine therapy for 5 years significantly reduced the incidence of HCC compared to placebo (3.9% versus 7.4%; hazard ratio, 0.49; P = 0.047).³¹

7. Correct answers: 1, 3 and 4

HCC is a tumor that is amenable for surveillance as tumors diagnosed during surveillance are smaller and more often amenable to treatment compared to tumors which are symptomatic.³² Surveillance using 6-monthly alpha fetoprotein (AFP) and ultrasound has shown significantly lower patient mortality rate of 83.2/100,000 compared to 131.5/100,000 in unscreened patients of chronic hepatitis.³³ Also, there is a well defined high risk groups in whom surveillance can be carried out.³⁴ Surveillance is recommended for patients with cirrhosis of any etiology who are eligible for effective treatment if diagnosed with HCC; patients with chronic HBV infection, age above 40 years, chronic HBV infection with family history of HCC; and patients with HCV infection with advanced fibrosis. Surveillance is unlikely to be beneficial in patients with Child C cirrhosis who are not candidates for liver transplantation.²⁵ Surveillance is not recommended for patients with NASH or NAFLD without cirrhosis, since HCC is rare in this group.³⁵

AFP should not be used for surveillance or to diagnose HCC as it has poor sensitivity and specificity and raised values may be due to active necro-inflammatory activity especially in patients with chronic viral hepatitis, rather than due to HCC.^36–38 FDG-PET should not be used for the diagnosis of HCC as it has low sensitivity (50%–70%) and especially low performance with well-differentiated HCC.^39,40

8. Correct answers: 1, 2 and 5

Orthotopic liver transplantation (OLT) is the best treatment for HCC as it results in complete removal of the HCC, removes the source of HCC development and restores liver function. Bridging therapy with loco-regional treatment is cost-effective and beneficial only if waiting time for OLT is expected to be longer than 6 months.^41,42 Tumors which are initially beyond conventional transplant criteria can be attempted to be down-staged using loco-regional therapies. OLT after successful down-staging results in excellent tumor-free and overall survival rates.⁴³ Other than tumor size AFP is an important predictor of recurrence after OLT. Total tumor diameter >8 cm and AFP >400 ng/mL are independent predictors of recurrence after OLT with AFP >400 ng/mL predicting an 8-fold increased risk of recurrence.⁴⁴ Resection is first-line treatment option in patients of cirrhosis with BCLC stage 0 HCC, very well-preserved liver function with hepatic venous pressure gradient (HVPG) ≤10 mmHg and good performance status.^25,45 Transarterial chemoembolisation with drug eluting beads (TACE-DEB) results in fewer side effects including hepatotoxicity and drug related adverse events compared to conventional TACE. It also resulted in better tumor response and improved survival in patients with advanced disease (Child–Pugh B, PST 1, and bilobar or recurrent disease) compared to conventional TACE.⁴⁶

9. Correct answers: 2 and 5

Persistent of hepatitis C virus (HCV) in the liver, lymphoid cells, or serum of individuals long after apparently successful therapy or spontaneous resolution of infection is called secondary occult hepatitis C infection (OCI). These patients have anti-HCV positivity and normal liver function tests. HCV RNA is usually detectable only by very sensitive nucleic acid amplification assays, either in peripheral blood or in liver tissue. Low-level HCV RNA positivity of unknown origin in patients with moderately elevated serum liver enzymes in the absence of anti-HCV detectable by standard clinical assays is known as cryptogenic OCI.⁴⁷ Patients with OCI may have ongoing viral replication, be infective and have liver damage on histology.^48,49 While all patients with OCI may not need treatment, cryptogenic OCI with persistent transaminitis may be treated with resultant normalization of liver enzymes and improvement in histology.^50,51

10. Correct answers: 2 and 4

Left lobe grafts have venous outflow drainage from the middle and left hepatic veins which drain via a common orifice which can be simply implanted into the recipient inferior vena cava. Also, most left lobe grafts have single biliary hepatic duct orifice and a single long left portal vein allowing for easier anastomosis during implantation. Also, donor morbidity is less after left lobe compared to right lobe resection.⁵²

However, left lobe transplant is more like to cause small for size syndrome (SFSS). A transplanted liver mass of about 1% of the recipient weight is required to maintain liver metabolic functions in the postoperative period. SFSS manifests as persistent ascites, cholestasis, coagulopathy, and encephalopathy following partial liver graft transplantation without a technical cause. SFSS results in higher incidence of septic complications and increased mortality. SFSS is uncommon if the graft recipient weight ratio (GRWR) is more than 1% and increases in frequency when GRWR is <0.8%.^53,54 A left lateral segment of a 60 kg adult, weighing around 250 g would hence suffice for a child weighing up to 25 kg. SFSS is thus common when left lobe grafts are used in adults. The partial graft is subjected to portal flow meant for a whole liver, leading to portal hyperperfusion. This leads to microvascular injuries to the graft.^55,56 Decreasing portal hyperperfusion to the graft by methods including shunts, splenic artery ligation and splenectomy can prevent SFSS.^57,58

Conflicts of interest

All authors have none to declare.