BASIC PREMISES OF PREVENTIVE GASTROENTEROLOGY
It is important to fulfill the following concepts:
- It should be seen as an important health problem (prevalence is high)
- Recognizable latent period
- Understanding the natural history
- Early detection by commendable clinical examination or investigations
- Should have effective preventive measures
- Standard accepted care of prevention
- Statistically significant—that early detection and treatment reduces morbidity and mortality
- Expected benefits exceed risk and cost
- Importance should not be given only to high prevalence of the diseases but where no specific curative treatment is available but simple preventive measure is available (glaring example is Hepatitis B vaccine)
- Day-to-day simple precautions like handwashing can impede/prevent and stop transmitting viral hepatitis (Fig. 1.1)
- Should (preferably) be cost effective.
Incidence of cirrhosis worldwide is not known. As per NIH (National Institute of Health), cirrhosis is the 12th leading cause of death in America. It affects men more than women. Not only the incidence is increasing due to various causes, peculiarly the incidence of cirrhosis is more due to peculiar acquisition of HCV through the mass use of tartar emetic given parenteral by same needle in many patients to eradicate schistosomiasis.
Definition of Cirrhosis (Fig. 1.2)
Cirrhosis is a condition in which the liver slowly deteriorates and malfunctions due to chronic injury. Scar tissue replaces healthy liver tissue, partially blocking the flow of blood through the liver.
Is cirrhosis preventable or reversible?
It is a most important and interesting topic that touches millions of lives. Because whatever that we have learnt for cirrhosis, it can be translated into today's practice with this deliberation.
The answer is
Preventable – YES
Importance of Etiology
Cirrhosis is the result of chronic liver damage from any cause. Diverse etiology can make it difficult to interpret patterns of this diagnosis and often a more detailed analysis of the underlying conditions is more informative. It would be intelligent thinking like putting jigsaw puzzle together that will give the diagnosis. It is easy to make a diagnosis if we follow golden rule of making diagnosis by history, clinical examination, and pertinent investigations. It will be as easy as solving jigsaw puzzle (Fig. 1.4).
The main reason to know the underlying cause is that it can forsee the development of cirrhosis, possible course, complications and possibly prognosis. It can conjure up all the aftermaths and complexities. These should be anticipated and avoided.
Epidemiology of cirrhosis is paripasu with epidemiology of its etiological fountain heads. When we take into consideration, various etiologies, particularly viral hepatitis, alcohol and obesity leading to fatty liver, it seems 10% of the population is expected to develop cirrhosis of liver.
The data is difficult to determine as 67% of patients have occult cirrhosis. Prevalence in the USA is estimated to be 0.15% of the population. The prevalence of liver disease in the European Union (EU) is estimated to be approximately 6%. Concrete data is difficult to compile.
Percent change in age-adjusted liver cirrhosis mortality between 1990 and 2000.2
Vitamin D3 deficiency is associated with advanced liver disease and low 25(OH) D3 levels are an indicator of a poor outcome and are associated with infectious complications.3 The epidemiological data by WHO in Europe has shown that cirrhosis accounted for 1–8% of all deaths in Europe. The incidence of cirrhosis in UK has increased from 12 to 16 per 100,000 person years from 1992 to 2001 (EASL: Burden of liver disease in Europe. The story for Asian-African countries is dismal with sizable incidence as high as 1% of the population, who may have histological cirrhosis).
We are surprised at the high prevalence of vitamin deficiency (VD) or insufficiency, even though we have abundant sunlight. (Is the theory that sunlight synthesizes VD valid or a superstition). There is need for screening of the population with chronic liver disease (CLD) for VD deficiency. Vitamin D supplementation could be safe and effective.4 I always give a course of vitamin D supplement as calcirol granules—1 sachet every weak for 6 weaks.
Incidence and Prevalence
Difficult to determines the exact incidence and or prevalence as the condition can remain clinically silent for many years. Unfortunately, there is no hard data to give this answer. One would also like to know the incidence of risk factors mainly being alcohol, Hepatitis B and C and then other minor causes like Wilson's disease or hemochromatosis. As the incidence is not exactly known, it is one of the common popular, social questions frequently discussed on print news media or, Facebook, without the final answer on the topic. Social media or newspapers always articulate concern over the increasing incidence of cirrhosis in India and this is quoted as well by different members of the Indian Society of Gastroenterology.
In reality there may be an increase in the incidence of cirrhosis worldwide.5 The incidence of clinically suspected or diagnosed cases of cirrhosis is approximately 1/1000.6 There has also been increased incidence with increase in age.7
Mortality Worldwide: It was responsible for 772,000 deaths in 2004, making it the 18th most common cause of death, there were 2660 deaths from cirrhosis of the liver in England and Wales in 2008.8
Nearly 88,000 people (approximately 62,000 men and 26,000 women) die from alcohol-related causes annually, making it the third leading preventable cause of death in the United States. (Alcohol Facts and Statistics-NIH-National Institute of Alcohol abuse and Alcoholism. Web site:www.niaaa.nih.gov)
In 2013, alcohol-impaired driving fatalities accounted for 10,076 deaths (30.8% of overall driving fatalities).
The next 10 years will see a dramatic change in the prevention of cirrhosis and its complications (Flow chart 1.1). The major thinking is in terms of reversing fibrosis or fibrosis index as the main culprit.
How does Fibrosis Behave?
Preventing or reversing fibrosis will be most welcome for all the physicians, hepatologists, and patients at large. Fibrosis is final outcome of injury (1st hit) induces inflammatory pathology-hepatitis (2nd hit) leading to the approiate background for fibrosis (Fig. 1.5). If we have drugs that will slow down or remove fibrosis, it will be most welcomed and will be like dream coming true.
With all that is at stake, it is important to understand and avoid the risk factors that contribute to cirrhosis. Whether a person is trying to prevent cirrhosis or manage the condition, understanding the risk factors like alcohol consumption, hepatitis and toxic exposure is critical.9
Non-alchoholic Fatty Liver Diseases
In today's time non-alchoholic fatty liver diseases (NAFLDs) is comparatively a new advent in the science of liver disease. After the first description by Dr Lugwig of Mayo Clinic, the knowledge has spread like a wild fire. The feeling that NAFLD is ubiqouitous occuring more or less all the countries particularly in the countries where obesity is prevalant. NAFLD signs and symptoms are usually not alarming. It has to be remembered as an important cause of liver affliction. Logical thinking will be that the incidence of NAFLD would be more, where obesity is more prevalent and associated with metabolic syndrome, type 2 diabetes, and hypertension. As has been covered in the earlier part of text, mortality in these cases is more due to chorionic villus sampling (CVS) emergency! Tissue diagnosis is not a must, as there are fairly trustworthy investigations, including liver function test (LFT), sonography, acoustic radiation force impulse (ARFI), CT or MRI. NAFLD as it progresses displays total spectrum covering hepatitis to cirrhosis leading to abundant complications. The treatment mainly hovers around reducing weight and insulin resistance by decreasing caloric intake and healthy calculated diet (Fig. 1.6).
Non-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic syndrome. Prevalence of metabolic risk factors including diabetes mellitus, obesity, etc. is rapidly increasing in India putting this population at risk for NAFLD. Patients with NAFLD are at increased risk for liver-related morbidity and mortality and also cardiovascular disease risk and increased incidence of diabetes mellitus on long-term follow-up. Management of patients with NAFLD may require a multidisciplinary approach involving not only the hepatologists but also the internists, cardiologists, and endocrinologists. This position paper which is a combined effort of the Indian National Association for Study of the Liver (INASL), Endocrine Society of India (ESI), Indian College of Cardiology (ICC) and the Indian Society of Gastroenterology (ISG) defines the spectrum of NAFLD and the association of NAFLD with insulin resistance and metabolic syndrome besides suggesting preferred approaches for the diagnosis and management of patients with NAFLD in the Indian context.
There is a settle difference of non-alcoholic fatty liver disease in east versus west as quoted by Swastik Agrawal, and Ajay Duseja from Department of Hepatology, Postgraduate Institute (PGI) of Medical Education and Research, Chandigarh, India. They quote: “Non-alcoholic fatty liver disease (NAFLD) is an important cause of liver disease worldwide with prevalence ranging from 10% to 30% in various countries. It has become an important cause of unexplained rise in transaminases, cryptogenic cirrhosis, and cryptogenic hepatocellular carcinoma. Pathogenesis is related to obesity, insulin resistance, oxidative stress, lipotoxicity, and resultant inflammation in the liver progressing to fibrosis. Pharmacological treatment in patients with NAFLD is still evolving and the treatment of these patients rests upon lifestyle modification with diet with lot of roughage, extra protein and exercise being the starting points of therapy (Fig. 1.7). While there are many similarities between patients with NAFLD from Asia and the West, there are certain features which make the patients with NAFLD from Asia stand apart. This review highlights the data on NAFLD from Asia comparing it with the data from the West.”10
Non-alcoholic fatty liver disease (NAFLD) has increased in parallel with central obesity, and its prevalence is anticipated to increase as the obesity epidemic remains unabated. NAFLD is now the most common cause of chronic liver disease in developed countries and is defined as excessive lipid accumulation in the liver, that is, hepatosteatosis. NAFLD ranges in severity from benign fatty liver to non-alcoholic steatohepatitis (NASH), and NASH is characterized by hepatic injury, inflammation, oxidative stress, and fibrosis. NASH can progress to cirrhosis, and cirrhosis is a risk factor for primary hepatocellular carcinoma (HCC). The prevention of NASH will lower the risk of cirrhosis and NASH-associated HCC. This study has focused on prevention of NASH. Authors have developed a model of NASH by using mice with the LDL cholesterol receptor gene ablated fed the Western diet (WD). The WD induces a NASH phenotype in these mice that is similar to that seen in humans and includes robust induction of hepatic steatosis, inflammation, oxidative stress, and fibrosis. With the use of transcriptomic, lipidomic, and metabolomic approaches, we examined the capacity of 2 dietary ω-3 (n–3) polyunsaturated fatty acids, eicosapentaenoic acid (20:5ω-3; EPA) and docosahexaenoic acid (22:6ω-3; DHA), to prevent WD-induced NASH. Dietary DHA was superior to EPA at attenuating WD-induced changes in plasma lipids and hepatic injury and at reversing WD effects on hepatic metabolism, oxidative stress, and fibrosis. The outcome of these studies suggests that DHA may be useful in preventing NASH and reducing the risk of HCC.11
Unfortunately for NASH, there is no specific treatment or preventive measures that are available which have been evaluated for prevention or its de novo occurrence in transplanted liver. Usual weight reduction by proper diet and exercise as well as taking care of metabolic syndrome is the corner stone.
Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is considered to be a hepatic manifestation of metabolic syndrome, and its incidence is rapidly increasing worldwide. It is currently the most common chronic liver disease. NASH can progress to liver cirrhosis and hepatocellular carcinoma, and may result in liver-related death. Currently, the principal treatment for NAFLD/NASH is lifestyle modification by diet and exercise. However, pharmacological therapy is indispensable because obese patients with NAFLD often have difficulty maintaining improved lifestyles (Figs 1.8 to 1.10). The pathogenesis of NAFLD/NASH has not been completely elucidated. However, insulin resistance, inflammatory cytokines, and oxidative stress are thought to be important in the development and/or progression of the disease. Currently, insulin sensitizers (thiazolidinediones) and antioxidants (vitamin E) seem to be the most promising therapeutic agents for NAFLD/NASH, and lipid-lowering drugs, pentoxifylline, angiotensin receptor blockers, and n-3 polyunsaturated fatty acids also have promise. However, there is a lack of consensus regarding the most effective and appropriate pharmacotherapy for NAFLD/NASH. Animal experiments suggest that herbal medicines and natural products may be promising therapeutic agents for NAFLD/NASH, but their efficacy and safety are yet to be investigated in human studies. In this paper, we review the existing and potential pharmacological therapies for NAFLD/NASH (Fig. 1.9).12
I wholeheartedly agree with the suggestion given by Wiegand and Berg6 that keeping an open eye to pick up cases of cirrhosis by the clinical criteria.
Fig. 1.8: The classical appearance of patient with non-alcoholic fatty liver disease and liver biopsy
Fig. 1.9: Archaic (age old) proverb-“Life expectency is inversely proportional to waist circumference” Usually related to cardiovascular problem; may be related to non-alcoholic fatty liver disease/non-alcoholic steatohepatitis
In suspected case, gynecomastia clinched the diagnosis. We should not wait only on transaminases or LFT in any given case may make it possible to pick up more cases of occult cirrhosis. It is also worthwhile to undertake abdominal ultrasonography (USG). In his article Wiegand has quoted work from a German state and drawn our attention to astounding figures that an altered gamma-glutamyl transpeptidase (GGT) is a useful prognostic marker.
MAIN CAUSES OF DEATH IN CIRRHOSIS
One has to realize that mortality in cirrhosis may not be related to cirrhosis but due to other etiologies, which may be more prevalent than causes due to primary cirrhosis itself:
• Cardiovascular diseases:
Is mortality due to liver failure in patients with NASH? Most of the patients with NASH may not die of hepatic failure but due to cardiovascular mortality
• Liver failure with bleed:
• Liver failure?—in view of crucial events in natural history of cirrhosis (considering mortality)—factors such as ascites, varices, progressive liver insufficiency
• Extrahepatic malignancies
For mortality in cirrhosis the clinical importance of infections in the outcomes of patients with cirrhosis is greatest.
• Other non-related causes
• Hepatocellular carcinoma (HCC)
• Other liver-related causes
Causes of Death in Cirrhosis
The different causes of death are listed in Table 1.1.
An algorithmic approach to the cirrhosis is shown in Flow chart 1.2.
Regretable Effects of Steatosis (Fatty Liver)
Histopathology of Cirrhosis showing Transversing Fibrosis
In Figure 1.11, the H & E stain showing thick collagen bands separating cirrhotic nodules. The H & E stain here is architectural distortion.
Pathological changes in the histological damage could have been prevented but, now it cannot be reversed.
Determined effort has to be made to detect risk factors.
Definition of “Risk Factor”
“A characteristic condition, behavior, habit, environmental or genetic factor that increases the possibility of a particular disease or injury”. Risk factor can also be defined as “something that increases your chances or likelihood of getting disease or condition”. It can very well be applied to the etiologies of cirrhosis of liver. We should know harmful etiologies (risk factors) to prevent each one of them (Table 1.2).
Majority of chronic insults to the liver can lead to cirrhosis. Mechanism of fibrosis may be different in different etiologies. Etiologies can be identified easily with careful history and pertinent investigations for different risk factors.
Fig. 1.11: Histopathology of non-alcoholic steatohepatitis going on to cirrhosisCourtesy: Dr Sarabjit Kaur, Dr Niraj Gujar, Dr Sushil Modkhar Kar, Breach Candy Hospital.
Determining etiologies is not only important for its prevention purposes but also its treatment for example in patient with hepatitis B, hemochromatosis, and Wilson. It can very well be a disease where family members should be screened. Family relatives with high risk for developing cirrhosis can be identified and cirrhosis can be prevented by appropriate steps. Age and gender has particular predilection for particular etiology and should be concentrated on surveillance.13,14 Complication is also determined by the etiologies, e.g. Hepatitis B and Hepatitis C cirrhosis. Vigilant observation for HCC is beneficial by early detection.
Given that liver transplantation entails a large economic outlay for relatively few individuals, the cost-effectiveness of the procedure, particularly in terms of the allocation of available livers and because cirrhosis is a progressive disorder, preventing or arresting its causes may substantially reduce the monetary burden of the disease effectively managing underlying diseases in order to slow the progression of cirrhosis to liver failure would be beneficial, assuming that such measures would not incur undue medical expenditures. However, even with management, cirrhosis may progress to liver failure, in which case liver transplantation will be required for the patient's survival.
Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma.
Core tip given by the authors: Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence (Fig. 1.12). Many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes.
Figs 1.12A and B: (A) Primary hepatoma with two daughter nodules. Early treatment of primary lesion could have inhabited the daughter secondary nodules; (B) HCC—obviously beyond surgical treatment as there is a spread in the portal vein. Early diagnosis and treatment could have curbed the spread which makes it inoperable. Possibly the hemi- hepatectomy might help
Therapy with interferon and nucleotide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for hepatitis B virus (HBV)-related HCC (Fig 1.13). In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation.15,16
Nodular hepatoma with portal vein invasion: It is already too late for curative treatment except possibly liver transplant.
Histological Behavior of Alcoholic Liver Diseases
The histological behavior of the alcoholic liver disease is shown in Figure 1.14.
Review by Vairappan describes the recent developments in the pathobiology of endothelial dysfunction (ED) in the context of cirrhosis with portal hypertension and defines novel strategies and potential targets for therapy.
Fig. 1.14: Histological behavior of alcoholic liver diseasesAbbreviation: HCC, hepatocellular carcinomaSource: EASL clinical practical guidelines: Management of alcoholic liver disease 2012
ED has prognostic implications by predicting unfavorable early hepatic events and mortality in patients with portal hypertension and advanced liver diseases. ED characterized by an impaired bioactivity of nitric oxide (NO) within the hepatic circulation and is mainly due to decreased bioavailability of NO and accelerated degradation of NO with reactive oxygen species. Furthermore, elevated inflammatory markers also inhibit NO synthesis and causes ED in cirrhotic liver. Therefore, improvement of NO availability in the hepatic circulation can be beneficial for the improvement of endothelial dysfunction and associated portal hypertension in patients with cirrhosis. Furthermore, therapeutic agents that are identified in increasing NO bioavailability through improvement of hepatic endothelial nitric oxide synthase (eNOS) activity and reduction in hepatic asymmetric dimethylarginine, an endogenous modulator of eNOS and a key mediator of elevated intrahepatic vascular tone in cirrhosis would be interesting therapeutic approaches in patients with endothelial dysfunction and portal hypertension in advanced liver diseases.17
Consequences of Portal Hypertension (Fig. 1.15)
Hepatic injury [leading to rise in serum glutamic pyruvic transaminase (SGPT)] can occur due to:
- Infection—virus (most common)
- Bacteria (rare)
- Fungus (rare)
- Liver congestion
Malnutrition in economically underprivileged countries is very prevalent. Severe malnutrition is strongly associated with deterioration of cirrhosis and increased mortality. Hypothetically these patients will be in Child–Pugh class A (Table 1.3). However, surprisingly it is not included in risk factors for cirrhosis.
CPT A: 5–6 points
CPT B: 7–9 points
CPT C: 10–15 points
Life expectancy (years)
Perioperative mortality (abdominal surgery) (%)
Abbreviation: INR, International normalized ratio.
Complications of Cirrhosis, their Prevention and Treatment
The complications of cirrhosis, and their prevention and treatment are listed in Table 1.4.
- Vasoconstrictors: Vasopressin, octreotide/somatostatin, terlipressin;
- Non-selective beta blockers: Nadolol, propranolol.
Placement of a small-diameter, covered stent (TIPSS procedure) to impede bleed from portal hypertension by self-expandable stent is shown in Figure 1.16.
Placement of a small-diameter, covered stent (TIPSS) is straightforward and prevented recurrent variceal rebleeding in patients with Child-Pugh A or B cirrhosis more effectively than drugs, which often required step-by-step-up therapy (Flow chart 1.3).
However, TIPSS did not increase survival time or quality of life and produced slightly more adverse events.18
- Helen Word, et al. Oxford Handbook of Epidemiology for Clinicians. Epidemiology of diseases—Cirrhosis of Liver. UK: Oxford Publication. 2012. p. 316, chapter 2.
- Mokdad AA, Lopez AD, Shahraz S, et al. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Medicine. 2014; 2005;12:14525(OH)].
- Finkelmeier F, Kronenberger B, Zeuzem S, et al. Low 25-Hydroxyvitamin D Levels are Associated with Infections and Mortality in Patients with Cirrhosis. Published online 2015 June 29. doi: 10.1371/journal.pone.0132119).
- Fernández NF, Torres LP, Joáo Matias D. Vitamin D deficiency in chronic liver disease, clinical-epidemiological analysis and report after vitamin D supplementation. Gastroenterol Hepatol. 2015 Nov 16. pii: S0210-5705(15)00245–9. doi: 10.1016/j.gastrohep.2015.10.003. [Epub ahead of print].
- Digestive disease in United States: Epidemiology and Impact. NIDDK, Bethesda, MD: 1994. NIH Publication No. 94–1447.
- Wiegand J, Berg T. The etiology, diagnosis and prevention of liver cirrhosis, Part of a series on liver cirrhosis. Disch Arzteb Int. 2013;110:85.
- European liver patient's Association, http://www.elpa-into.org. April 2005.
- Williams R. Global challenges in liver disease. Hepatology. 2006;44:521–6.
- Painter FM. Can cirrhosis be prevented? Frankp@chiro.org.
- Arawal S, Duseja AK. Non-alcoholic fatty liver disease: East versus west. J Clin Exp Hepatol. 2012;2:122–34.
- Takahashi Y, Sugimoto K, Inui H, Fukusato T. Current pharmacological therapies for non-alcoholic fatty liver disease/non-alcoholic steatohepatitis. World J Gastroenterol. 2015;21:3777–85.
- Schuppan D, Afdhal NH. Liver cirrhosis. Lancet. 2008;371:838–51.
- Jansen PL. Liver disease in the elderly. Best Pract Res Clin Gastroenterol. 2002;16:149–58.
- Vairappan B. Endothelial dysfunction in cirrhosis: Role of inflammation and oxidative stress. World J Hepatol. 2015;7:443–59. Published online 2015 Mar 27.
- Sauerbruch T, Mengel M, Dollinger M, et al. Prevention of rebleeding from esophageal varices in patients with cirrhosis receiving small-diameter stents versus hemodynamically controlled medical therapy. Gastroenterology. 2015;149(3):660–8. doi: 10.1053/j.gastro.2015.05.011.