3
Global Perspective

Arulraj Ramakrishnan¹, Grace L.‐H. Wong², and Innocent K. Besigye³

¹ Kovai Medical Center and Hospital, Coimbatore, Tamil Nadu, India

² Chinese University of Hong Kong, Hong Kong SAR, China

³ College of Health Sciences, Makerere University, Kampala, Uganda

KEY POINTS

Abnormal liver function tests (LFTs) are prevalent universally, but they may related to the prevalence of certain infections/conditions prevalent in that country or region.
In many healthcare systems, primary care is not developed.
Globally, liver specialists are scarce and interpretation and management of LFTs are done by hospital generalists.
History, examination, and awareness of common conditions prevalent locally enables management of abnormal LFTs in a cost‐effective manner.
Alcohol‐related liver disease and non‐alcoholic fatty liver disease (NAFLD) are on the rise in India, and, together with viral hepatitis, contribute to the majority of abnormal LFTs.
Drug‐induced liver injury in India, particularly the use of complementary and alternative medicine use, needs to be considered during evaluation of LFTs.

Introduction

The commonly used term “liver function tests,” is best termed “liver tests” because these tests are markers of liver disease rather than measures of liver function. The standard liver tests include aspartate aminotransferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), bilirubin, gamma glutamyl transferase (GGT) and albumin. Liver tests are inexpensive and are a good predictor of not only mortality from liver disease but also mortality from other cause. ALT has been proved more useful in the evaluation of hepatic disease because it is found in greater concentration in the liver than in other organs. Since they are neither specific nor indicative of any particular disease, further testing is usually required to define the cause and extent of disease. This can be done either by extensive testing or by using a more focused approach (estimated costs of US$448 vs. US$502/patient, respectively), with both identifying the aetiology in only 55% of cases [1]. An assessment of the patient with suspected or clinically obvious liver disease is not only context dependent but also location and cost dependent. Generic algorithms for the evaluation of liver disease may not be applicable universally because not only does the history and examination aid interpretation of abnormal LFTs but also the country of origin of the patient is essential. As a number of conditions are more prevalent in some parts of the world, this chapter provides an overview from India, the Far East, and Africa. Since abnormal liver tests and their patterns are covered in Chapter 1, the focus in this chapter is on common patterns of abnormal liver tests seen in practice (Figure 3.1):

Schematic illustration of simplified response to abnormal liver tests in India. — **Figure 3.1** Simplified response to abnormal liver tests in India.

Isolated raised bilirubin (e.g. Gilbert syndrome, hemolysis).
Cholestatic; predominantly raised ALP and GGT, such as primary biliary cholangitis (PBC), biliary obstruction, hepatic congestion and drug‐induced liver injury.
Hepatitic; predominantly raised ALT and AST, such as viral hepatitis,, alcohol‐related liver disease (ARLD), autoimmune hepatitis (AIH), and drug‐induced liver injury (DILI).
Infiltrative, such as tuberculosis (TB), malignancy.

Indian Perspective

The burden of liver disease according to etiology and stage is not available, even from the developed‐country population‐based studies. Studies have tried to define normal values of transaminases for Indian population, but most laboratory values are based upon Western populations and those provided by the manufacturers of kits. Presentation of liver disease in India is often late. It occurs in young people and accounts for one fifth (18.3%) of all cirrhosis deaths globally [2]. Epidemiological data from Indian population‐based studies on the prevalence of abnormal liver tests, their etiology, and fibrosis, are also scarce. Hepatitis B (33.3%), is the most common cause of chronic liver disease in India [3], followed by hepatitis C (21.6%), alcohol (17.3%), and NAFLD (12.8%), but alcohol (34.3%) is the most common cause when stratified by the presence of cirrhosis. Significant regional heterogeneity exists between different regions of India, viral hepatitis B and C being more common in northern and eastern regions compared with southern regions, where alcohol is more common.

Patterns of Specific Liver Disorders in the Indian Context

Viral Hepatitis

In India during 2011–2013, 804 782 viral hepatitis cases and 291 outbreaks were reported. Among the outbreaks with known etiology, 48% were caused by hepatitis E virus (HEV), 33% hepatitis A infection (HAV), 12% hepatitis A and E, and 7% hepatitis B or C [4]. Viral hepatitis contributes to 43% of acute liver failure in India, with HEV contributing to 29.5%, hepatitis B virus (HBV) 7.4%, HAV 2%, and dual (HAV and HEV) infection accounting for 3.9% [5]. Viral hepatitis most often produces a hepatic pattern of liver injury (AST and ALT level elevations predominate). Some patients are asymptomatic with normal aminotransferase levels but may still be infected chronically with HBV or hepatitis C virus (HCV). Interpretation of abnormal viral markers is essential in countries with high endemicity like India to avoid confusion between active infection and immunity.

Hepatitis A Infection

HAV is a single‐stranded, non‐enveloped RNA virus belonging to the family Picornaviridae, classically spread via the fecal–oral route. HAV is defined as an acute illness with a discrete onset of any sign or symptom consistent with acute viral hepatitis (e.g. fever, headache, malaise, anorexia, nausea, vomiting, diarrhea, abdominal pain, or dark urine) with (i) jaundice or elevated total bilirubin levels ≥ 3.0 mg/dl, or (ii) elevated serum ALT levels > 200 iu/l, and (iii) the absence of a more likely diagnosis [6]. Acute HAV infection is confirmed by immunoglobulin (Ig) M antibody to hepatitis A virus (anti‐HAV) positivity (Table 3.1). Acute HAV infection is generally mild and subclinical but contributes to 2% of acute liver failure [5] in India. Most infections are managed with supportive care. Patients develop lifelong immunity (IgG) to HAV following early childhood asymptomatic HAV infection [7]. HAV vaccination is not recommended in India [7] because of high endemicity, except for patients with decompensated chronic liver disease awaiting transplant and those who are immunosuppressed (inactivated vaccines are preferred).

Table 3.1 Hepatitis A antibody tests and different clinical situations.

Infection state	Total anti‐HAV (IgG, IgM)	Anti‐HAV IgM
Acute HAV	Positive	Positive
Resolved HAV	Positive	Negative
Immunization	Positive	Negative

HAV, hepatitis A infection; Ig, immunoglobulin.

Hepatitis B Infection

HBV is a double‐stranded DNA virus belonging to the family Hepadnaviridae. It has a prevalence of 2% in India. Transmission is predominantly from an infected mother to her child, from inoculation injury, or horizontal transmission at young age, with sexual and parenteral transmission (e.g. via blood transfusions, intravenous drug abuse) contributing to a minority of cases.

Acute HBV infection is diagnosed by the onset of signs or symptom consistent with acute viral hepatitis (e.g. fever, headache, malaise, anorexia, nausea, vomiting, diarrhea, and abdominal pain), and either jaundice, or elevated serum ALT levels above 100 iu/l. It is confirmed by the presence of hepatitis B surface antigen (HBsAg) and positive immunoglobulin M antibody to hepatitis B core antigen (anti‐HBc) [6]. The majority of patients with acute infection will remain asymptomatic and only 30% develop icteric hepatitis. Acute HBV infection as a cause of acute liver failure is possibly decreasing over time in India.

Chronic HBV in endemic areas is incidentally found in asymptomatic persons with no evidence of liver disease or may have a spectrum of disease ranging from chronic hepatitis to cirrhosis or liver cancer. Chronic HBV is characterized by persistence of HBsAg for longer than six months with positive anti‐HBc (IgG) and negative hepatitis B surface antibody (anti‐HBs). Hepatitis B envelope antigen (HBeAg) positivity usually indicates active viral replication and liver injury. HBeAg becoming negative and development of hepatitis B envelope antibody (anti‐HBe) over time is associated with lesser viral replication (lower levels of HBV DNA and transaminase values), and less (or no) hepatic inflammation. HBV DNA level and HBeAg status are used to determine the need for treatment and play a crucial role in estimating the response to treatment [6].

HBV reactivation occurs in patients with previously documented resolved HBV, or with the low replicating HBsAg (carrier) state. It is characterized by sudden increase in HBV replication or the reappearance of active inflammatory disease of the liver. Reactivation is usually triggered by immunosuppression or chemotherapy in the host or spontaneously. Clinical manifestations can vary from a transient, clinically silent, disease to liver failure. HBV reactivation diagnosis is dependent on the HBV disease state before activation. In patients with resolved HBV (negative HBsAg and positive anti‐HBs), decline in anti‐HBs and the reappearance of HBsAg indicates reactivation. In low replicating HBsAg (carrier) state, reactivation is diagnosed by a rise in the serum HBV DNA or a rise in the serum ALT levels.

Table 3.2 summarizes the serological tests used in assessment of hepatitis B infection and its interpretation. Treatment recommendations are beyond the scope of this chapter; suffice to say that newer antiviral drugs (such as entecavir and tenofovir) have a high barrier to resistance and decrease morbidity and mortality in HBV infection. The World Health Organization (WHO) recommends HBV vaccination in routine immunization programs because vaccination prevents HBV infection and decreases the incidence of chronic liver disease and hepatocellular carcinoma. Vaccination in India is essential for household contacts of people who are HBsAg‐positive and those undergoing dialysis.

Table 3.2 Interpretation of hepatitis B serologic test results.

Source: Adapted from US National Notifiable Diseases Surveillance System. Surveillance Case Definitions for Current and Historical Condition [6].

Interpretation	Test	Result
Susceptible	HBsAg	Negative
	Anti‐HBc	Negative
	Anti‐HBs	Negative
Immune due to natural infection	HBsAg	Negative
	Anti‐HBc	Positive
	Anti‐HBs	Positive
Immune due to hepatitis B vaccination	HBsAg	Negative
	Anti‐HBc	Negative
	Anti‐HBs	Positive
Acutely infected	HBsAg	Positive
	Anti‐HBc	Positive
	IgM anti‐HBc	Positive
	Anti‐HBs	Negative
Chronically infected	HBsAg	Positive
	Anti‐HBc	Positive
	IgM anti‐HBc	Negative
	Anti‐HBs	Negative
Interpretations unclear 4 possibilities:	HBsAg	Negative
1. Resolved infection (most common)	Anti‐HBc	Positive
2. False positive	Anti‐HBs	Negative
3. “Low level” chronic infection
4. Resolving acute infection

anti‐HBc, antibody to hepatitis B core antigen; anti‐HBs, hepatitis B surface antibody; HBsAg, hepatitis B virus surface antigen; Ig M, immunoglobulin M.

Hepatitis C

HCV is an enveloped, single‐stranded RNA virus belonging to the family Flaviviridae, which has six genotypes. Genotype 3 is the most common (61.8%) in India, followed by genotype 1 (31.2%). Although the estimated prevalence of HCV is low, at 0.5%, with one fifth of the world’s population, India accounts for a large proportion of the worldwide HCV burden. The predominant modes of transmission of HCV in India are unsafe therapeutic injections and blood transfusions. Acute HCV infection is usually asymptomatic, or only produces mild, non‐specific, flu‐like symptoms, and is infrequently diagnosed in the acute phase, with spontaneous clearance in about 15% of infected patients. Chronic HCV is characterized by presence of one or more of jaundice, peak elevated total bilirubin levels ≥ 3.0 mg/dl, or peak elevated ALT levels greater than 200 iu/l [6]. Three tests are commonly used to define hepatitis C status: anti‐HCV antibody, HCV RNA, and HCV genotyping. Anti‐HCV is used for screening but, for confirmation, HCV RNA is performed (Table 3.3). Although treatment recommendations are beyond the scope of this chapter, it should be emphasized that newer antiviral drugs will not only decrease the morbidity and mortality due to HCV infection but will also help with eradication.

Hepatitis D

Hepatitis D virus (HDV) is an RNA virus that encodes for a hepatitis D antigen (HDAg). HDV infection requires the presence of HBV infection and can be acquired as either a co‐infection (simultaneously with HBV) or a superinfection (on a pre‐existing HBV infection). HDV infection is spread via the parenteral route but is infrequent in India. Treatment is predominantly of the superinfection or co‐infection of HBV.

Hepatitis E

HEV virus is a positive‐stranded non‐enveloped RNA virus belonging to the family Hepeviridae. HEV is primarily spread via the fecal–oral route and is the most frequent cause of acute viral hepatitis in India [4]. HEV infection is not only the most common cause of acute liver failure in India [5]

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