Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State in The Gambia

Diabetes,

diabetic ketoacidosis and hyperosmolar hyperglycemic state in The Gambia

Team MFH

Medics for Humanity

The Gambia

Abstract

Diabetes mellitus affected 451 million people and caused around 1.6 million direct deaths worldwide in 2017. Diabetes is rising fastest in low- and middle-income countries, where access to adequate prevention, diagnosis and treatment is often lacking, additionally posing a heavy burden to the health systems. In particular, diabetic ketoacidosis is the most frequent hyperglycemic complication in patients with diabetes mellitus, and the main cause of death among diabetic children and adolescents. Hyperosmolar hyperglycemic state is also an hyperglycemic emergency with a high mortality rate. This article aims to provide some insights into the epidemiology, pathogenesis, treatment, prevention, and management of diabetes and hyperglycemic emergencies, with a particular focus in The Gambia. Moreover, we aim to bring attention to the topic, expand the general knowledge, and promote collaboration among the different actors involved in healthcare of diabetic patients in this country.

Introduction

Diabetes mellitus is a group of metabolic disorders characterized by high blood sugar levels over a prolonged period with alterations of carbohydrate, fat, and protein metabolism, resulting from defects in insulin secretion, insulin action, or both (1). The symptoms of diabetes mellitus include frequent urination, increased thirst, blurred vision, and weight loss. Often the symptoms are not severe, or may be even absent, but still the hyperglycaemia is sufficient to cause pathological and functional changes before the disease is diagnosed, with deleterious consequences (1). If left untreated, diabetes can cause many complications. Severe acute complications include diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), coma, or even death. Serious long-term complications include damage, dysfunction and failure of various organs such as cardiovascular and cerebrovascular disease, nephropathy that may lead to chronic kidney disease, foot ulcers, damage to the eyes (retinopathy with potential blindness), degeneration of weight bearing joints (neuropathic arthropathy), and features of autonomic dysfunction, including sexual dysfunction (2).

Diabetes occurs either when the pancreas does not produce insulin or when the body cannot effectively use the insulin it produces. There are three main types of diabetes mellitus. Type 1 diabetes, previously denominated insulin-dependent or juvenile diabetes, results from the pancreas’s failure to produce insulin due to immune-associated loss of pancreatic beta cells, and its cause remains unknown. Researchers agree that type 1 diabetes results from a complex interaction between genes and unknown environmental factors (2). Type 2 diabetes, formerly called non-insulin-dependent or adult-onset diabetes, is a heteregoneous and complex disease that accounts for over 90% of all diagnosed cases, and begins with insulin resistance, a condition in which cells fail to properly respond to insulin. As the disease progresses, a lack of insulin may also develop. The most common risk factors are a combination of excessive body weight and insufficient physical activity. Other risk factors for type 2 diabetes include older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, and ethnicity. Type 2 diabetes is increasingly being diagnosed, along with obesity, in children and adolescents (3). Gestational diabetes is the third main form and occurs when pregnant women without a previous history of diabetes develop any degree of hyperglycaemia, which usually resolves after the birth of the baby (4). Less frequent types include latent autoimmune diabetes in adults (LADA), maturity-onset diabetes of youth (MODY), secondary diabetes mellitus, and others (5).

Prevention and treatment of diabetes involve maintaining a healthy diet, regular physical exercise, a normal body weight, and avoiding the use of tobacco. Studies have shown that medications have been successful in preventing diabetes in some population groups (6). The major components for the treatment of diabetes are diet and exercise, oral hypoglycaemic therapy, and insulin therapy (2). Control of blood pressure and proper foot care are also crucial for people with the disease. Type 1 diabetes must be managed with insulin injections, while type 2 may be treated with medications with or without insulin. Insulin and some oral medications can cause low blood sugar.

In 2017, there were 451 million people with diabetes worldwide -around 8.5% of the world adult population- and almost half of them were undiagnosed cases (7,8). The trend suggests that rates will continue to rise up to 552 million by 2030 (9). The highest diabetes prevalence is observed in North America and the Caribbean region (11.5%), followed by the Middle East and the North African region (10.7%) (10). Diabetes is associated with a two- to three-fold increase in all-cause mortality, mainly attributed to cardiovascular diseases (11). In 2016, an estimated 1.6 million deaths were directly caused by diabetes (8). The global healthcare expenditure in diabetes was estimated to be around US$850 billion in 2017, with a predicted substantial increase by 2030 (7,12). For example, in the case of the US, the cost of care for people with diabetes now accounts for around 1 in 4 dollars spent in healthcare (13).

Diabetes is therefore a global health problem that has reached the status, together with obesity, of ‘the biggest epidemic in human history’ (14). Diabetes is rising fastest in low- and middle-income countries, where it already affects 336 million people (15). However, conventional risk factors cannot fully explain the higher prevalence of diabetes in low-income countries (16). Diabetes is more likely to be undiagnosed or poorly treated in low- and middle-income countries, where it poses a double burden together with infections (15). Interactions between diabetes and infectious diseases such as tuberculosis or malaria have been described (15).

Even if the technologies and medicines to enable people with diabetes to live healthy lives exist, still region and country-income level determine the national capacity to prevent and control diabetes. Although most countries have national diabetes policies, in lower-income countries these policies and guidelines often lack funding and implementation, as revealed by the World Health Organization (WHO) (2). Only one third of low- and middle-income countries have reported general availability of basic technologies for diabetes diagnosis and management, such as blood and urine glucose measurement, in primary health-care facilities, in contrast to more than 90% of high-income countries (2). Similarly, only 23% of low-income countries have reported that insulin is generally available in publicly-funded primary-care facilities vs. 96% of high-income countries (17). In addition, national population-based data are lacking, since less than half of the countries have included blood glucose measurement in surveys evaluating the prevalence of physical inactivity, overweight and obesity in the past years (2).

In the case of sub-Saharan Africa, rapid demographic, sociocultural, and economic transitions are behind the increased risk and prevalence of diabetes and other non-communicable diseases (18). Unfortunately, the true burden of diabetes and its macrovascular and microvascular complications in sub-Saharan Africa remains widely unknown (18). Medics for Humanity (https://medicsforhumanity.org) is a non-profit medical organization aiming to tackle the diabetes gap in sub-Saharan Africa, with the majority of its activities currently developed in The Gambia. The Gambia is a small country in West Africa with 2.1 million inhabitats in 2017, of which 48.6% live below the national poverty line, reaching almost 70% in rural areas, and 10.6% are below the international poverty line of 1.90 dollars (19). According to WHO, diabetes is also a public health problem in The Gambia, with a prevalence of 6.5% in men and 5.2% in women, and accounting for 2% of the total registered deaths (20). In 2014, the total expenditure on health per capita in the country was 118 international dollars, for a total of 7.3% of the GDP (21). Diabetes poses a great economic burden in the country, with more than 3.6% of the annual health budget spent on the treatment of these patients (22). Awareness of diabetes mellitus among diabetic patients in The Gambia remains poor, according to a previous study that showed that only around half of the affected individuals knew what diabetic mellitus is, had some knowledge of the causes, and was aware about the methods of prevention (23). These results highlighted the need of improving health education and promotion in the country as part of the strategy to prevent, manage and control diabetes mellitus (23). Since the beginning of 2018, Medics for Humanity has been working in various locations together with hospitals and communities in The Gambia, with the goal to provide optimal diabetes care, including appropiate medical treatment. Our organization has established polyclinics that perform the necessary follow-up visits and try to provide people with the required standard of treatment, including laboratory examinations and follow-up discussions with the patients. During our clinical practice in The Gambia, we have observed frequent cases of DKA and HHS, severe complications of diabetes known as hyperglycemic emergencies, which we discuss in the following section.

Hyperglycemic emergencies: focus in The Gambia

DKA and HHS are the two most common life-threatening acute metabolic complications of diabetes mellitus. DKA consists of the biochemical triad of hyperglycemia, ketonemia and high anion gap metabolic acidosis, and most often occurs in those with type 1 diabetes, but also in type 2 patients under stressful conditions, such as trauma, surgery, or infections (24). DKA is the main cause of death among diabetic children and adolescents, reaching up to 13% mortality in low-income countries due to associated cerebral edema, sepsis, shock and renal failure (25). In rural areas of sub-Saharan Africa, DKA-associated mortality can be even higher, as one study conducted in South Africa demonstrated, with a death rate of 17.4%, with two thirds of deaths occurring in type 2 diabetic patients (26). In a study conducted in Benin, more than 75% of children and adolescents presented with DKA as the first manifestation of type 1 diabetes mellitus (27). Moreover, DKA at diagnosis of type 1 diabetes in children has been recognized as a predictor of poor long-term glycemic control (28).

DKA occurs in the setting of hyperglycemia usually as a consequence of insulin deficiency, which causes unchallenged lipolysis and oxidation of free fatty acids, resulting in ketone body production and subsequently increased anion gap metabolic acidosis (29). Insulin defficiency in the bloodstream prevents glucose absorption, inhibiting the production of oxaloacetate through reduced levels of pyruvate, and finally leading to dangerous glucose and ketone levels in the blood. The presence of glucose in the urine, or glucosuria, leads to osmotic diuresis, dehydration and hyperosmolarity. Severe dehydration, if not properly compensated, may lead to impaired renal function. Hyperglycemia, osmotic diuresis, serum hyperosmolarity, and metabolic acidosis result in severe electrolyte disturbances, which can result in an augmented osmolarity in brain cells that clinically manifests as an alteration in the level of consciousness (30). The mechanisms leading to DKA are shown in Figure 1.

DKA is a potentially life-threatening complication if it is not timely identified and treated. Common risk factors that can precipitate the development of extreme hyperglycemia and subsequent ketoacidosis are infection; non-adherence to insulin therapy; acute major illnesses like myocardial infarction, sepsis, or pancreatitis; stress; trauma; and medications such as glucocorticoids or atypical antipsychotic agents, which can affect carbohydrate metabolism (29).

Patients with DKA develop a variety of symptoms usually within several hours of the inciting event, including abdominal pain and symptoms of hyperglycemia (polyuria, polydipsia, polyphagia, and more severe presentations including unintentional weight loss, dehidratation, vomiting, weakness, and mentation changes). Dehydration and metabolic abnormalities lead to lethargy, obtundation, and even respiratory failure, coma, and death (29). Although no international agreement exists on the diagnostic criteria for DKA, several parameters have been proposed, including: ketonaemia ≤3 mmol/L by ketone meter, or significant ketonuria (more than 2+ on standard urine sticks); blood glucose over 11 mmol/L or known diabetes mellitus; and venous bicarbonate <15 mmol/L and/or venous pH<7.3 (31,32).

Initial treatment of DKA is based on appropriate fluid replacement to restore circulatory volume, clear ketones and correct electrolyte imbalance, followed by insulin administration (31). Intravenous diabetic medication is usually administered to these patients due to discontinuity of insulin therapy due to hospitalization. Long-acting insulin analogues are normally administered during the initial management of DKA in order to provide background insulin when intravenous administration is interrupted (31). Importantly, successful DKA management requires strict monitoring of clinical and laboratory parameters (including blood ketones, venous pH and bicarbonate, and renal function), together with identification and treatment of precipitating events. Immediately after recovery, the focus should be in preventing future occurrences of DKA, and therefore patients should be educated on the disease, attend scheduled follow-ups for careful assessment and monitoring, and have access to medicine supplies. Frequent monitoring of ketone levels allows early detection of ketosis and administration of appropiate insulin doses that prevent serious hyperglycemia attacks.

Since the management of DKA is complex, a list of milestones have been proposed for each phase (33). During phase I (0-6 h), history and physical examination, together with initial laboratory studies, need to be performed, and a monitoring plan should be implemented. The patient should receive an intravenous bolus of isotonic fluids and, following, start insulin therapy if potassium levels are over 3.3 mmol/L. During phase II (6-12 h), biochemical and clinical monitoring continue. Isotonic fluids can be changed to hypotonic fluids if sodium levels are corrected, and potassium should be maintained in the 3.3-5.3 mmol/L range. The insulin infusion rate has to be adjusted as necessary and, if glucose levels are under 200-250 mg/dL, dextrose has to be added to intravenous fluids. During the last phase, phase III (12-24 h), biochemical and clinical monitoring continue, and therapy needs to be adjusted to avoid further complications. It is important in this phase to address the precipitating factors, and to move from intravenous to subcutaneous insulin if DKA resolves. Finally, a consultation with a diabetes educator should be planned (33).

The true burden of DKA in sub-Saharan Africa remains largely unknown but, contrary to Western countries, this complication is also frequent among type 2 diabetes patients of African origin (34). The main causes of DKA in patients in sub-Saharan Africa were identified as newly diagnosed diabetes, missed insulin doses (due to unavailability and unaffordability of insulin, missed clinics, illness perception, and use of alternative therapies like herbs, prayers and rituals) and infections (such as urinary tract infections, tuberculosis and pneumonia), being insulin deficiency the major underlying mechanism (35). In an Ethiopian study, 65% of the patients presented recurrent DKA with two or more episodes (36).

In The Gambia, a study conducted several years ago showed that only 25% of diabetic patients received insulin, being DKA the major cause of death in this population (22). A retrospective study presented in 2015 showed that more than 60% of children admitted to The Edward Francis Small Teaching Hospital (Banjul, Gambia) with a diagnosis of type 1 diabetes mellitus had DKA on presentation (37).

Acute kidney injure is a rare but potentially fatal complication of DKA associated with severe dehydration. A retrospective conducted study in France showed that 50% of patients with severe DKA presented acute kidney injury on admission, and most of them were in a high risk class (38). A direct correlation between DKA and acute kidney injury has been also confirmed in the pediatric type 2 diabetes population, according to a study in the US (39). DKA has been associated with a deterioration of kidney and liver function parameters (40). In cases of acute kidney injury, renal replacement therapy for patients with DKA has been proposed to have the potential to improve outcomes. Moreover, diabetes and high blood pressure are the most common causes of chronic kidney disease, with about 25% of adults with diabetes in the US presenting kidney disease (41). To make things more complicated, end-stage renal disease has been shown to increase the rates of adverse glucose events when treating DKA or HHS (42). In the case of The Gambia, the situation is critical for patients with kidney disease since only one dialysis center exists in the whole country, and there is a clear shortage of resources, such as dialysis catheters, which are expensive for the general population. Medics for Humanity has started a collaboration with Edward Francis Hospital in Banjul aiming to prevent kidney disease by initiating early diagnoses and treatment of illnesses or conditions, such as diabetes and DKA, which contribute to kidney failure, and to make dialysis accessible and affordable to all patients with kidney failure in The Gambia.

The second hyperglycemic complication, HHS, mainly occurs in people with type 2 diabetes with very high blood glucose levels, often over 40 mmol/L. Symptoms include urination, thirst, nausea, dry skin, disorientation and, in later stages, drowsiness and a gradual loss of consciousness (43). HSS consists of moderate to variable degrees of clinical ketosis, usually detected by nitroprusside method, and the frequent presence of consciousness without coma (44). The mechanisms leading to HHS are shown in Figure 1. Clinically, DKA and HHS differ by the severity of dehydration, ketosis and metabolic acidosis.

Although less frequent than DKA, HHS has a higher mortality rate that can reach up to 5-10% and is explained by severe dehydratation, older age, and presence of comorbid conditions in these patients (44). The most commonly observed causes of HHS include serious cardiovascular disease, acute stroke, infections (in particular genitourinary and/or respiratory infections), and conditions preventing the patient from adequate water intake during osmotic diuresis, which can lead to the development of HHS over a course of weeks (45). HHS can also emerge as a consequence of inappropriate medication therapy or under certain social conditions, being often the first manifestation especially in type 2 diabetes (45).

The main focus on HHS management is effective volume repletion and normalization of serum osmolarity. The therapeutic approach for the treatment of HHS is similar to the one recommended for DKA, with the difference that no bicarbonate therapy is required for HHS, and that the change to glucose-containing fluid is performed when blood glucose reaches 300 mg/dL (44).

Data on HHS from sub-Saharan Africa are scarce, particularly in rural areas. A study conducted two decades ago in South African diabetic patients admitted to a hospital with hyperglycaemic emergencies showed that infection was the leading precipitating cause for both HHS and DKA, followed by first presentation and non-compliance (46). A majority of the patients (55.2%) presented type 2 diabetes, and the mortality rates were 16.6% for HHS and 6.8% for DKA (46). A more recent study about hyperglycemic emergencies in southwest Ethiopia showed a higher frequency for DKA than for HHS (93% of patients experienced DKA), with a majority of type 1 diabetic patients (64%). The most common precipitating causes were infections (59%), non-compliance to medications (32.3%), and newly diagnosed diabetes (23.6%) (47). In a study in Nigeria, DKA and HHS occured in 85% and 15% of patients with hyperglycaemic emergencies, with mortality rates of 18% and 35%, respectively (48). Unfortunately, although we have faced several cases of HHS during our clinical activities in The Gambia, no data have been reported regarding the prevalence, mortality, causes, or other aspects of this diabetic complication in the country. More research is needed to fully understand the extent of hyperglycemic emergencies in diabetic patients in The Gambia, and to improve the management of this life-threatening complication.

 Conclusions

Diabetes mellitus is a global health problem posing a great burden in low- and middle-income countries. DKA is one of the most frequent complications in patients with diabetes mellitus, and the main cause of death among diabetic children and adolescents. Although less frequent than DKA, HHS has a higher mortality rate. Our non-profit organization, Medics for Humanity, is working in The Gambia together with local hospitals and institutions in order to improve the access of diabetic patients to early diagnosis, treatment -including hemodialysis-, and health education, and to avoid the development of serious complications such as DKA and HHS.

 Conflicts of interest

The authors declare no conflicts of interest.

 

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