The findings of our study demonstrate the relatively early age at presentation for patients with both liver cancer and cirrhosis as well as the unequal sex distribution for both conditions in Ghana. We describe the performance of APRI score and AFP in ESLD and identify financial constraints as a potential factor resulting in insufficient diagnostic workup. We additionally report the clinical stages at presentation, providing evidence that these patients mostly present with late stage disease. Furthermore, our study describes the causes of ESLD in Ghana, highlighting the disease burden of hepatitis B virus infection.
The median age at diagnosis of 44 years for liver cancer among study participants is consistent with findings from previous studies in which it has been demonstrated that HCC patients in sub-Saharan Africa present at a younger age than patients in other parts of the world (9, 12). This has been attributed in part to the difference in etiology, in that hepatitis C and alcoholic liver disease are more frequent causes of liver cancer in Europe and the Americas, compared with sub-Saharan Africa. That being said, in China where similar to Ghana, the main cause of HCC is HBV infection, the age at presentation is still higher (13). It has been suggested that differences in oncogenicity of the prevailing HBV genotypes in sub-Saharan Africa, coupled with host genetic and environmental factors such as dietary exposure to aflatoxin, could play a role in the progression of disease, and contribute to the differences in age at onset of HCC. Additionally, there is growing evidence of the role of the gut microbiome in liver disease progression, and the microbiome is known to vary across ethnicities owing to several factors including diet, lifestyle, and socioeconomics (14). Studies related to the gut microbiome in ESLD have largely been conducted in the developed world, and it would be useful to explore similarities and differences in the microbiomes of ESLD patients in an African cohort compared with those from the Western world, in an attempt to better understand liver disease dynamics.
The median age at diagnosis for cirrhotic patients was 46 years, similar to the findings of a single-center study conducted at the Korle Bu Teaching Hospital in Accra, Ghana, in which the mean age of patients was 45 years (11). This figure has not changed significantly in almost 15 years, confirming that cirrhosis affects individuals during their most productive years of life (15). Although the economic impact of the burden of disease has not been fully enumerated in Ghana, there is evidence from countries in which preventive and treatment strategies do exist, that there is a high economic burden and significant loss of productivity associated with the diagnosis of liver cirrhosis (16). Other studies in Asia and the Americas demonstrate a mean age at diagnosis of cirrhosis of about 60 years, over a decade older than observed in Ghana (17, 18).
The higher male to female ratio was not surprising, as it has been consistently demonstrated that this gender disparity exists, particularly for HCC. It is unlikely that health seeking behavior of patients accounts for this gender disparity, as women more readily utilize outpatient services in Ghana (19). Of the few studies that have investigated why more males than females develop HCC, one study described the influence of estrogen in reducing interleukin-6 and subsequently reducing tumorigenesis (20), whilst a more recent study suggested that the cause might be related to the fact that men produce lower levels of the hormone adiponectin (21).
The median APRI scores among HCC and cirrhotic patients were 1.5 and 1.4 respectively, both below the recommended cutoff value of 2 for non-invasive diagnosis of cirrhosis among adults in low resource settings. Moreover, this cut-off demonstrated low sensitivity for diagnosing cirrhosis in our cohort. This is important because cirrhosis is one of the indications for starting antiviral treatment in patients with chronic hepatitis B infection. The rationale for the relatively high cut-off value is that using a low cut-off would result in a larger number of false positives, and that patients in need of antiviral therapy who have an APRI of <2 would likely fulfil other eligibility criteria such as high ALT or HBV DNA levels (22). However, as demonstrated in our results, the majority of patients were unable to afford HBV DNA testing, and relying on this result as the cue for initiating therapy when APRI is <2 may result in missing opportunities for treatment. Additional studies validating the APRI score and other non-invasive tests of fibrosis and cirrhosis in Ghana and other sub-Saharan African countries are warranted, since only one sub-Saharan African country was included in the validation of APRI and the subsequent recommendations. Furthermore, studies to identify the optimal criteria for initiation of antiviral treatment for chronic hepatitis B infection in sub-Saharan Africa are needed.
The cost of tests was a notable barrier to optimal care. The majority of patients reported a household income of less than GHC 1000 ($182). Putting this into context, a patient would typically spend GHC 650 ($118) or more on currently recommended tests such as HBV DNA, AFP, and INR alone, irrespective of whether they are enrolled in the National Health Insurance Scheme in Ghana. It is known that inability to afford diagnostic tests hinders not only clinical management, but also the ability of public health systems to adequately assess and characterize the burden of disease in low- and middle-income countries (23). AFP performed well in distinguishing HCC from cirrhosis, thus ensuring the test is made affordable for patients could potentially increase HCC surveillance among at-risk patients in Ghana.
Hepatitis B infection was the primary risk factor for ESLD among patients in Ghana, reflecting the high burden of chronic hepatitis B infection in Ghana. The national prevalence of HBV infection is 12.3% (24), demonstrating high endemicity in the country. Efforts to reduce HBV prevalence have focused on immunization of infants against hepatitis B since the year 2002, however there remains a large older cohort of individuals who did not receive vaccination, and are therefore still at risk of development of HBV-related end-stage liver disease. Additionally, the threat of mother to child transmission still exists, since birth-dose vaccination and immunoglobulin administration for newborns are still not routinely practiced in Ghana. Strategies must be developed to manage these challenges in order to reduce the morbidity of HBV infection and ESLD in the region.
The sero-prevalences of antibodies to HCV were 3.7% among persons with cirrhosis and 6.4% among those with HCC. Other studies have reported estimates between 2.7-8.7% for cirrhosis and 6% for HCC (9, 11, 25). Although the prevalence of HCV-related liver disease is lower than in other countries such as Egypt and the United States, HCV treatment is not readily available in Ghana, and access to treatment is further hindered by the need for expensive tests, including HCV viral load and genotyping. Public health advocacy and education are therefore still necessary to reduce the threat of HCV infection in Ghana.
Both cirrhotic and HCC patients presented with advanced disease. Sixty percent of HCC cases had multinodular lesions. This is not an uncommon finding in sub-Saharan African countries. Yang et al. in 2017 reported that 84% of liver cancer cases presented with multinodular disease (9). In Ghana, Gyedu et al. found that only 8% of persons with HCC seen at the Komfo Anokye Teaching Hospital in Accra between 2007-2013 were eligible for curative treatment (10). In our study, the AFP performed well as a diagnostic test in the detection in HCC. This highlights the urgent efforts needed to develop strategies that will improve liver cancer surveillance in Ghana, in order to enhance eligibility for curative treatment and reduce mortality.
This is also true with respect to cirrhosis surveillance in patients with known risk factors, because our results showed that cirrhotics predominantly presented with Child-Pugh class B and C. Furthermore, high APRI score and weight loss were significantly associated with a high Child-Pugh score at presentation. In Ghana, a lack of nutritional assessment and local nutritional guidelines were found to contribute to poor nutritional management of cirrhosis patients (26), and this may potentially contribute to the high proportion of patients with weight loss. For patients who may not be able to perform necessary diagnostic tests, surrogates such as weight loss and high APRI may be useful in understanding the degree of morbidity and the risk of mortality, although more studies are needed in this regard in Ghana. The causes of weight loss and sarcopenia in ESLD are multifactorial and include reduced synthesis of glycogen, increased protein breakdown, malnutrition and other factors (27). Treatment is therefore multifaceted, and pharmacologic and nutritional management are important for patients presenting with significant weight loss.
One of the major limitations of the study was the inability of patients to afford particular diagnostic tests, which limited the derivation of clinical scoring for severity of Child-Pugh and BCLC scores. To elaborate, this study relied on abdominal ultrasound for diagnosis of cirrhosis, since elastography is not yet performed in Ghana, and patients must pay for liver biopsies out of pocket. As a result, it is possible that patients with Child-Pugh Class A cirrhosis were underreported. Likewise, due to financial constraints, the majority of patients could not afford abdominal CT scans with intravenous contrast, therefore clinicians relied on abdominal ultrasonography, which has lower sensitivity and specificity, for the diagnosis of HCC. It is therefore possible that cases of early HCC were less readily identified. A further limitation in measuring AFP levels is the fact that patients receiving HBV therapy were not captured, and it is known that HBV therapy may reduce AFP levels in the bloodstream.
Additional limitations to this study include the fact that patients were recruited from the teaching hospital outpatient departments, thus inpatient ESLD patients, who typically have higher morbidity, were not included in the study. It is therefore possible that the overall disease severity of patients with ESLD is worse than we observed here. Furthermore, no patients with Grade 3 encephalopathy or higher were recruited because they were clinically unstable, and this would also have affected our ability to comprehensively ascertain the clinical characteristics of the patient cohorts; however, the study provides an accurate representation of the burden of liver disease seen in the ambulatory outpatient setting. Finally, this study was conducted at public teaching hospitals in Ghana. It is possible that patients who seek traditional and alternative medicine (TAM) are not accounted for in this study, which may cause some selection bias, however it is important to add that symptomatic ESLD patients are also referred from these facilities once non-allopathic care is not successful.