A holistic approach to the patients/Families with inborn errors of metabolism

For practical reasons, this article focuses on treatable IEMs, which does not exclude that untreatable IEMs can be approached from a holistic perspective. However, tertiary prevention, and palliative medicine in particular, are specialties by themselves that follow a holistic approach (1), and that is why individuals with untreatable IOMs should always be transferred to a palliative team.

Treatable IEMs represent many groups of disorders – each group containing several diagnoses – with a broad spectrum of clinical manifestations (acute vs. chronic onset of reversible or irreversible signs and symptoms), prognosis (from infaust to normal), and different pathways of inheritance, treatment, and outcome (2), where each group, and sometimes even each disorder needs special expertise. Besides, within each disorder, there can be interindividual genotypic and phenotypic variability from severe to potentially benign metabolic phenotypes (3). On the other hand, treatable IEMs share significant facets: (a) they are inherited, i.e. may cluster within families and are transmitted over generations with the probability of recurrence (b) they are chronic conditions, often associated with the necessity of lifelong day-to-day management, taking into consideration the general health status as well as growth and development, (c) management is most often multimodal, including diet, drugs, and skilled behavior, (d) management is executed by the family and/or the patients themselves, however, guided by an experienced metabolic team, (e) close and reliable mutual feedback between management and guidance is essential for effective and efficient monitoring of treatment and outcome.

The word “ὅλος,” in Greek means “entire, the whole” (why sometimes the term wholistic is used), or “integrally”. An intuitively easier understanding can be gained from the perspective of general systems theory (4, 5), defining the structure of a system as a set of elements (parts) that are connected by relations. The elements can get inputs from outside of the system or from other elements within the system and can produce outputs. A system is called open when not all elements get inputs and produce outputs. In addition to the structure, systems can be described by their function. For example, looking at the urea cycle from a systems perspective, the structure consists of four biochemical compounds (ornithine, citrulline, argininosuccinate, and arginine) plus five core enzymes, one activating enzyme, and one antiporter, whereby the function is the detoxification of ammonia (input) to urea (output). The fact that elements plus relations define a system is why it is said that the whole is more than the sum of its parts (elements).

If the elements are active, i.e. influencing other elements, the system is called dynamic. A dynamic system that can maintain its structure and function is called to be in a steady-state, and it is stable if it can return to its initial state after a disturbance. Inputs and outputs can be material (like in the urea cycle), information (e.g. explaining the result of newborn screening to parents), or both (e.g. monitoring systems for inborn errors of metabolism (6) or transition programs from pediatrics to adult medicine (7).

So far it should become obvious that what is meant by the “whole” can and must be explicitly described, and that expressions like “everything is a system” or “everything is related to everything” are not very helpful, as they do not allow to distinguish different systems, but end up with one single system (what is called “the total approach” in contrast to the “holistic approach”). Systems should be described (and organized) in the most parsimonious way, which still allows adequate functioning. For example, when a laboratory result is communicated via the doctor to a patient, the information flow is transitive (i.e. if the lab sends a result to the doctor, and the doctor communicates the result to the patient, thenthe information from the lab is transmitted to the patient as the final receiver), but this will not mean that the lab is in direct contact with the patient.

There are also other concepts describing similar ideas. For example, in 2016, the Archive of Disease in Childhood published a series of articles (8, 9, 10, 11) dealing with the “integrative care model,” which avoids fragmentation between and within public services, by creating an “umbrella team,” making moves toward integration of infant, children, and young people’s health services (8). However, this model is a generic political and organizational framework focused on the UK health system, and it has to be translated to specific diagnoses (12).

The holistic structure and thereby the boundaries of a system is defined by its function or aim. The aim of the holistic approach to families/patients with IEMs is to provide the best evidence-based diagnostic service, treatment, and care in the most efficient way, given economic, technical, personnel constraints of the health care delivering team as well as the individual background of the patient, where treatment refers to what medical measures are possible and necessary to manage the disease of an individual patient, and care refers to how the treatment of the individual patient has to be managed, as well as additional para-medical interventions.

In the field of IEMs, the family subsystem should be conceptualized as the extended genetic family. On the one hand, the family is a resource system, giving practical, technical, and emotional support to the patient but also informational support to health care professionals (HCPs), but a family member with an IEM may also be a risk for other family members, e.g. leading to emotional and financial parental stress (20, 21) or affecting healthy sibling’s mental health and psychosocial adjustment (22). On the other hand, inherited diseases create the need for genetic counseling. Roughly one index case with an autosomal recessively inherited trait may be associated with nine other people seeking genetic information (1 sibling of the case, 2 parents, 1 sibling of the parents and its spouse, 4 grandparents).

Figure 1 shows a prototypical professional health care team for patients with an IEM. Teams for inpatients and outpatients in metabolic centers usually will constitute the primary point of care, but often external HCPs also consult. Not all medical and para-medical specialties will necessarily be involved with any IEM and depending on the specific diagnosis, severity of the genetic, biochemical, metabolic, and clinical condition of the patient the team will be larger or smaller. Professional teams can and should change with chronological and developmental age when new developmental tasks for the patients arrive. For most disorders, nursery-school and school teachers will be involved, at least informed about the basics of the condition. Programs of transition from pediatric to adult medicine may involve a transfer to a completely new professional team. However, for all IEMs a close and reliable loop from the clinical setting to the metabolic laboratory and back to the clinical setting is essential.

Figure 1

Regional, national, or even international patient advocacy groups exist for nearly every IEM. They organize meetings in person and newsgroups and chatrooms on the internet, are represented in political institutions, and trigger research or medical guidelines

(23). Patients and parents can find new peer groups but also get role models for coping with different aspects of their condition at different ages or situations. HCPs should be aware that also patient organizations get sponsored from pharmaceutical industries potentially creating conflicts of interest (24).

Metabolic medicine is impossible without hardware and software, partly extremely expensive and difficult to handle (amino acid analyzers, mass spectrometers, sequencers), partly low priced and easy to manage (food scales). Medical aids such as nasogastric tubes, syringe pumps, speech computers, or orthoses require individual adaptation and training, extending the team temporarily.

Like every approach to IEMs also the holistic approach is more or less regulated by laws (definition of screening panels, definition and equipment of reference centers, the legislation of genetic testing and counseling, abortion, transition politics, etc.), constituting constraints of the system as a whole. On the other hand, in most legislations individuals with chronic conditions have special rights (e.g. tax concessions, compensation for disadvantage, inclusion in school and society) however, only after individualized examination and allowance, so social workers are essential in a holistic approach. Scientific societies, but also patient organizations may also be involved in legislation.

There are many aspects regarding care for IEMs. Newborn screening panels are evaluated for cost-effectiveness (31), regulations regarding reimbursement of medical food and drugs are different between legislations sometimes leading to significant co-payment and loss of social and economic opportunities of patients and families (32). Finally, investment in a team of specialists only pays off for larger centers.

In a series of publications in The Lancet (33, 34, 35), three roles of the industry have been formulated. The industry as an informant providing medical information (1), as a political player (2), and as a medicines provider (3). In fact, diagnosis, treatment, and care will not be possible without the industry. However, obligations to shareholders on the one hand and the community on the other may be imbalanced leading to efforts to mold medical thinking as a means to enlarge the market (36).

Having defined the elements of the holistic approach, it remains to determine how these elements are related and how the system is controlled. From a formal point of view, 10 elements can have (10 × 9)/2 = 45 binary relations, leading to a system where every element is directly related to each other. Although this is true in principle, many relationships are indirect. Individual patients are members in patient advocacy groups, and these groups are political players in health legislation, but not every patient will be involved in this process. Biochemists are necessary to run the metabolic laboratory, but will not be in personal contact with the individual patient, scientists will transfer their results via HCPs to the patient. On the other hand, there may be unexpected direct relationships, e.g. between individual patients and the industry in cases of direct selling or direct-to-consumer advertising.

IEMs are very different, not only regarding the impairment of the metabolic pathway requiring different treatment, but also regarding the state of scientific research, clinical experience, and implementation into health systems (2). Besides, the phenotypic spectrum of diseases can be vast. Last, not least individuals with the same disease can be very diferent, more or less skilled to manage a diet or taking blood samples at home, anxious or optimistic, have a small unsupportive or a large supportive social network, be symptomatic or asymptomatic. Therefore, in the same way as treatment has to be individualized, also care and the holistic approach should be individualized. This leads to the question of who will establish, control and steer the system.

The team of HCPs described in Figure 1 is in the center of the holistic approach responsible for the management of the patient and the training and guidance of the person. The holistic approach is established by this team and optimally organized as a disease and case management program based on evidence-based guidelines, describing what has to be done as to why, how, when and by whom (25, 27, 37, 38). Such programs will also allow measures of quality assurance and quality control, improving not only the treatment of the individual but also the health system (29).