DBA is a rare, genetically driven anaemia, characterised by a high sensitivity of erythroid precursors to apoptosis [5]. Although there might be an initial response to corticosteroid therapy and eligibility of some cases for bone marrow transplantation, it is estimated that more than 30% of the patients will require chronic blood transfusions [6]. A leading complication of transfusion therapy is iron overload, an important cause of death among DBA patients [3]. This is the first case reporting an ACLF in a DBA patient in which acute liver damage (mainly related to congestive heart failure) overlapped chronic liver disease (promoted by iron deposits and consequent fibrosis).
The concept of ACLF encompasses the simultaneous acting of both acute and chronic insults to the liver, which can result from a wide range of triggers [7]. Recently, the need for including ‘cirrhosis’ in the definition of ACLF was discussed, since patients with advanced liver disease – but not necessarily cirrhosis – exhibit similar mortality rates compared to cirrhotic patients during the clinical course of ACLF [8]. Our patient, in spite of not being cirrhotic, already had evidence of chronic and progressive hepatic disease.
The difference between ACLF and decompensated cirrhosis is the systemic inflammatory response, which determines a slower recovery and a higher mortality in patients with ACLF compared to those adjudicated as having just decompensated cirrhosis [9, 10]. The precipitating factors may be the same [11]. Objectively, there is a score (CLIF-OF) based on six organ failures (hepatic, renal, haemodynamic, coagulation, neurological and respiratory) [12] to classify patients into the following categories: decompensated cirrhosis, grade 1, grade 2 or grade 3 ACLF. Mortality in 28 days in subjects with grade 1, 2 and 3 ACLF is about 20, 55 and 86%, respectively [9, 13]. Knowledge of the CLIF-OF score is quite important, as it is used to calculate the CLIF-C ACLF score, which is currently the best predictor of mortality in patients with advanced fibrosis and acute liver deterioration [14].
Our patient was admitted with an uncommon myriad of initial signs and symptoms that involved both the heart (dyspnoea, lower limbs oedema) and the liver (ascites, jaundice, coagulopathy). The autopsy was crucial for diagnostic confirmation, since there was a microscopic overlap of chronic and acute liver injuries. Clearly, most of her chronic heart and liver lesions were related to massive iron deposits. Furthermore, the main feature responsible for the acute liver decompensation seemed to be heart failure, as we found signs of the recent death of hepatocytes near the centrilobular vein (i.e. passive congestion). The role of cardiac failure as a precipitating event in ACLF has already been established; sadly, it is also a determinant of a worse prognosis, probably due to haemodynamic changes [15, 16].
Although potentially reversible, ACLF is a severe condition, and the outcome mainly depends on hepatic reserve and the prompt treatment of the dysfunctions. In our case, an advanced stage of liver fibrosis was observed at the autopsy, which compromised liver recovery and may have contributed to the outcome [7]. In addition, liver microscopy presented other features of the so-called ‘histological pattern 1’, with ductular proliferation, the presence of bile plugs and pericellular fibrosis, which can also determine unfavourable survival [7]. Finally, it is known that on ACLF, hepatocytes rely on haematopoietic stem cells to regenerate [7, 17]. This recruitment was probably impaired in the scenario of DBA and this may have been another contributing factor to a bad outcome.
There was a notable association between a tooth infection and the start of the major symptoms in our patient. Usually, a dental infection without systemic involvement is not expected to be a trigger for heart decompensation, but it has already been reported that oral infections are associated with the onset of pro-inflammatory states [18]. In patients with previous heart lesions, this inflammatory trigger may culminate in neurohormonal activation and acute events, such as thromboembolism or myocardial damage [19]. It is not clear whether this was really the trigger or if there was also another unidentified factor. It is noteworthy that in more than 30% of decompensated heart failures, no precipitating factor has been identified [20].
The management of patients with DBA is challenging. With the exception of cases eligible for bone marrow transplantation, there is no definitive cure [21]. Therefore, throughout the years of assisting these patients, clinicians often face moral decisions that illustrate the ‘trolley dilemma’ in medicine [22]. In this setting, chronic blood transfusions help, to some extent, in stabilising the patient’s anaemia. But even with chelation therapy, the inevitable consequence is a progressive iron deposition that may involve multiple systems [1]. Previously reported cases illustrate that secondary haemochromatosis is a constant feature in children and adults with DBA who are chronically submitted to blood transfusions, leading to dysfunctions in several organs and even to malignancies, such as hepatocellular carcinoma [23, 24].
The present case is quite representative, as we found iron deposits not only in the heart and liver but also in the lungs, spleen, thyroid, pancreas, adrenal glands and bone marrow. Therefore, the secondary haemochromatosis could explain the diabetes and hypothyroidism, and may have contributed to earlier respiratory failure. Interestingly, we found iron not only in macrophages, but also in parenchyma cells (e.g. cardiomyocytes, hepatocytes). This is a mark for long-term iron overload, and is a worrisome feature due to the toxic effect of this metal in parenchyma cells [23, 25].
To our knowledge, this is the first case reporting the sequence: DBA, multiple blood transfusions, secondary haemochromatosis, advanced liver fibrosis, heart failure, ACLF and death. A multidisciplinary team is essential to care for DBA patients, since there is a significant emotional burden related to a chronic disease, hard access to medications and arduous insertion in the labour market due to expected absences. This can lead to poor adherence to therapy and subsequent ineffective iron chelation, but the consequences of massive iron deposition may be severe. In fact, the retrospective study of Janov et al. (1996) [26] found a median overall survival of only 38 years for DBA patients, which reflects the difficulties in the management of these patients. In this context, we must emphasise that bone marrow stem cell transplantation should be performed in eligible patients as soon as possible. Less harmful treatments, such as gene therapy [27], are in development and may represent a new era in the management of DBA.
